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The search for human obesity genes

Affiliation.

1 Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245-0549, USA. [email protected]
PMID: 9603720
DOI: 10.1126/science.280.5368.1374

Understanding of the genetic influences on obesity has increased at a tremendous rate in recent years. By some estimates, 40 to 70 percent of the variation in obesity-related phenotypes in humans is heritable. Although several single-gene mutations have been shown to cause obesity in animal models, the situation in humans is considerably more complex. The most common forms of human obesity arise from the interactions of multiple genes, environmental factors, and behavior, and this complex etiology makes the search for obesity genes especially challenging. This article discusses the strategies currently being used to search for human obesity genes and recent promising results from these efforts.

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A new pathway connecting diet, genetics and body weight found in Stanford Medicine-led study

A study in mice found a connection between the amino acid taurine and an enzyme called PTER — highlighting a metabolic pathway that links diet, genetics and body weight.

August 7, 2024 - By Krista Conger

Shellfish is a rich source of taurine, an amino acid that has been associated in some studies with reductions in body weight and improvements in endurance exercise. sum41 / stock.adobe.com

A new biochemical pathway linked to diet and body weight hints at the possibility of a new class of anti-obesity drugs, Stanford Medicine researchers and their colleagues have found.

The study, conducted in mice, found a relationship between a previously unstudied body weight-associated gene called PTER and an amino acid called taurine, which has been associated in some studies with reductions in body weight and improvements in endurance exercise.

The newly identified relationship highlights a body weight-regulating metabolic pathway independent of the mechanisms of weight loss drugs like Ozempic or Wegovy, suggesting the two approaches could work in tandem to one day provide additional options for weight control in people.

“This is an additional branch of a very complex system of feeding and body weight regulation,” said Jonathan Long , PhD, an assistant professor of pathology. “We all want to know, ‘What should I eat? When should I eat it? How does it affect me?’ But many diet-based studies offer confusing information. We are trying to answer this question in a more concrete way — starting with molecules, then pathways, then working our way up to the physiology.”

Long is the senior author of the study , which was published Aug. 7 in Nature . Postdoctoral scholar Wei Wei , PhD, is the lead author of the research.

Weight, nutrition and hunger: a complex relationship

The complicated web of interactions that govern when we get hungry, what and how much we eat, and how much we weigh is exceedingly difficult to untangle. Previous research in Long’s laboratory uncovered a relationship between an “anti-hunger” molecule called lac-phe produced after vigorous exercise and the diabetes drug metformin that can cause moderate weight loss.

In the new study, Wei and Long focused on taurine, which is abundant in protein-rich foods such as meat and shellfish. Taurine supplementation in mice can lower body weight and enhance exercise performance. Conversely, mice genetically engineered to have low levels of taurine show muscle atrophy and a decreased capacity for exercise. But exactly how taurine has these effects has been unclear.

Jonathan Long

“Taurine does all sorts of stuff in our bodies, and is metabolized in many different ways,” Long said. “It’s a complicated soup.”

One byproduct, or metabolite, of taurine is called N-acetyltaurine, which is formed when taurine and another molecule called acetate are combined. Levels of N-acetyltaurine in the body fluctuate in response to physiological changes — including endurance exercise and diet — that affect taurine and acetate levels.

As they were exploring taurine metabolism and its relationship to body weight, Wei and Long identified an enzyme called PTER, for phosphotriesterase-related, that converts N-acetyltaurine back into taurine. (Many metabolic pathways can run both forward and backward — a molecular seesaw that allows the body to respond nimbly to changes in diet, exercise and other variables.)

The gene that encodes PTER is part of a panel of genes that have been associated with body mass index in humans. Mutations in one, MC4R, cause people to feel hungry all the time and are strongly associated with obesity. But many of the others, including PTER, have remained mysterious.

“Despite this genetic association, no one really knew what the PTER did or why it was linked to body mass index in humans,” Long said. “It was an orphan gene that encoded an orphan enzyme. Now we know that PTER breaks down, or hydrolyzes, N-acetyltaurine.”

Teasing out molecular effects

When Long and Wei studied mice in which the PTER gene had been knocked out, they found that the animals had higher levels of N-acetyltaurine in their blood and tissues than control mice — a not unexpected finding when PTER is missing. When they were fed a diet high in fat, and given taurine in their drinking water, the mice without PTER ate and weighed significantly less than the control animals after eight weeks. The difference in body weight was due entirely to a reduction of fat mass in the knockout animals, the researchers found.

Next, they tested whether giving the mice N-acetyltaurine directly had a similar effect. They found that a daily dose of N-acetyltaurine reduced body weight and food intake in both PTER knockout mice and the control animals fed a high-fat diet.

Further studies showed that the PTER pathway is independent of the pathway used by the GLP1 receptor agonists, such as Ozempic, currently on the market.

This is a fundamental advance in understanding how we eat affects our weight and our bodies.

“This is a complicated interaction of genetics and diet that can regulate the body weight of these animals,” Long said. “This is a fundamental advance in understanding how we eat affects our weight and our bodies.”

Interestingly, it’s not clear how N-acetyltaurine is made. It is possible that the gut microbiome plays a role. The researchers found that mice treated with antibiotics for one week to kill off much of their gut bacteria had 30% less N-acetyltaurine circulating in their bodies than before treatment.

“This possible role of the gut microbiome is interesting in the context of research into the rational manipulation of our intestinal bacteria for health,” Long said. “Perhaps we could one day have probiotic or dietary interventions that promote the formation of N-acetyltaurine to reduce body weight. But much more work needs to be done.”

Long and his colleagues are continuing their studies of PTER and taurine metabolites in people. The task is daunting but exciting.

“All of the stuff we eat, and we eat a lot of stuff, can interact with our bodies at a molecular and genetic level,” Long said. “It’s not a simple code. But we’re starting to understand these intersecting pathways at a much more granular level than ever before.”

Researchers from the Massachusetts Institute of Technology; the University of California, Irvine; and the Arc Institute of Palo Alto contributed to the study.

The work was supported by the National Institutes of Health (grants DK105203, DK124265, DK111916 and K99AR081618), the Stanford Diabetes Research Center, the Stanford Cardiovascular Institute, the American Heart Association, the Jacob Churg Foundation, the Weintz Family COVID-19 Research Fund, the Wu Tsai Human Performance Alliance, the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, the Ono Pharma Foundation, and the Stanford Maternal and Child Health Research Institute.

Stanford University has filed a provisional patent application on PTER-N-acetyltaurine for the treatment of cardiometabolic disease.

Read a Q&A with Jonathan Long about his research.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Scientists Identify Rare Gene Variants That Can Increase Your Risk of Obesity by up to 500%

New research conducted by the Medical Research Council (MRC) has identified genetic variants in two genes that have some of the largest impacts on obesity risk discovered to date.

The discovery of rare variants in the genes BSN and APBA1 are some of the first obesity-related genes identified for which the increased risk of obesity is not observed until adulthood.

The study, published in Nature Gene t ics , was led by researchers at the MRC Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge.

The researchers used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in over 500,000 individuals.

They found that genetic variants in the gene BSN , also known as Bassoon, can raise the risk of obesity as much as six times and was also associated with an increased risk of non-alcoholic fatty liver disease and of type 2 diabetes.

The Bassoon gene variants were found to affect 1 in 6,500 adults, so could affect about 10,000 people in the UK.

The brain’s role in obesity

Obesity is a major public health concern as it is a significant risk factor for other serious diseases, including cardiovascular disease and type 2 diabetes, yet the genetic reasons why some people are more prone to weight gain are incompletely understood.

Previous research has identified several obesity-associated gene variants conferring large effects from childhood, acting through the leptin-melanocortin pathway in the brain, which plays a key role in appetite regulation.

However, while both BSN and APBA1 encode proteins found in the brain, they are not currently known to be involved in the leptin-melanocortin pathway. In addition, unlike the obesity genes previously identified, variants in BSN and APBA1 are not associated with childhood obesity.

This has led the researchers to believe that they may have uncovered a new biological mechanism for obesity, different to those we already know for previously identified obesity gene variants.

Based on published research and laboratory studies they report in this paper, which indicates that BSN and APBA1 play a role in the transmission of signals between brain cells, the researchers suggest that age-related neurodegeneration could be affecting appetite control.

Professor John Perry, study author and an MRC Investigator at the University of Cambridge, said:

“These findings represent another example of the power of large-scale human population genetic studies to enhance our understanding of the biological basis of disease. The genetic variants we identify in BSN confer some of the largest effects on obesity, type 2 diabetes, and fatty liver disease observed to date and highlight a new biological mechanism regulating appetite control.”

The use of global data

The accessibility of large-scale databases such as UK Biobank has enabled researchers to search for rare gene variants that may be responsible for conditions including obesity.

For this study, the researchers worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico. This is important as the researchers can now apply their findings beyond individuals of European ancestry.

If the researchers can better understand the neural biology of obesity, it could present more potential drug targets to treat obesity in the future.

Dr Slavé Petrovski, VP of the Centre for Genomics Research at AstraZeneca, said:

“Rigorous large-scale studies such as this are accelerating the pace at which we uncover new insights into human disease biology. By collaborating across academia and industry, leveraging global datasets for validation, and embedding a genomic approach to medicine more widely, we will continue to improve our understanding of disease – for the benefit of patients.”

Next steps for research

Professor Giles Yeo, study author based at the MRC Metabolic Diseases Unit, added: “We have identified two genes with variants that have the most profound impact on obesity risk at a population level we’ve ever seen, but perhaps more importantly, that the variation in Bassoon is linked to adult-onset and not childhood obesity. Thus these findings give us a new appreciation of the relationship between genetics, neurodevelopment and obesity.”

Reference: “Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease” by Yajie Zhao, Maria Chukanova, Katherine A. Kentistou, Zammy Fairhurst-Hunter, Anna Maria Siegert, Raina Y. Jia, Georgina K. C. Dowsett, Eugene J. Gardner, Katherine Lawler, Felix R. Day, Lena R. Kaisinger, Yi-Chun Loraine Tung, Brian Yee Hong Lam, Hsiao-Jou Cortina Chen, Quanli Wang, Jaime Berumen-Campos, Pablo Kuri-Morales, Roberto Tapia-Conyer, Jesus Alegre-Diaz, Inês Barroso, Jonathan Emberson, Jason M. Torres, Rory Collins, Danish Saleheen, Katherine R. Smith, Dirk S. Paul, Florian Merkle, I. Sadaf Farooqi, Nick J. Wareham, Slavé Petrovski, Stephen O’Rahilly, Ken K. Ong, Giles S. H. Yeo and John R. B. Perry, 4 April 2024, Nature Genetics . DOI: 10.1038/s41588-024-01694-x

Neuronal nightmare: the troubling connection between sugar, obesity, and brain degeneration, the ancient survival mechanism driving today’s obesity crisis, newly identified genetic variant predisposes people to slimness, bmi is a more powerful risk factor for diabetes than genetics – losing weight could prevent or even reverse diabetes, kl001 interacts with cryptochrome, may offer a new way to treat diabetes, 3-d image shows how dna packs itself into a “fractal globule”, “area x” of zebra finch may provide insights to human speech disorders, researchers induce magnetism to a non-magnetic organism, researchers complete genome sequence of a denisovan human finger bone.

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Robust single nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity

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Single nucleus RNA sequencing (snRNA-seq), an alternative to single cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the biological processes involved in adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.

Competing Interest Statement

The authors have declared no competing interest.

Figures S2 and S7 have been updated to provide a comprehensive comparison between the data from this study and previous studies; Figure S6 has been revised to include additional data on adipocyte nucleus profiles; the list of authors has also been updated.

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RESEARCH HIGHLIGHT
29 July 2021

Obesity genes open new avenues of research

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Karen O’Leary is an Associate Research Analysis Editor with Nature Medicine.

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Obesity accounts for a major burden of disease globally, and has a heritable component. However, previous efforts to define the genetics of obesity have failed to unearth rare variants associated with a large physiological effect; achieving this will require a large-scale sequencing-based approach.

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Study finds a new pathway connecting diet, genetics and body weight

by Krista Conger, Stanford University

A new biochemical pathway linked to diet and body weight hints at the possibility of a new class of anti-obesity drugs, Stanford Medicine researchers and their colleagues have found.

The study, conducted in mice , found a relationship between a previously unstudied body weight -associated gene called PTER and an amino acid called taurine , which has been associated in some studies with reductions in body weight and improvements in endurance exercise.

"This is an additional branch of a very complex system of feeding and body weight regulation," said Jonathan Long, Ph.D., an assistant professor of pathology.

"We all want to know, 'What should I eat? When should I eat it? How does it affect me?' But many diet-based studies offer confusing information. We are trying to answer this question in a more concrete way—starting with molecules, then pathways, then working our way up to the physiology."

Long is the senior author of the study , which was published Aug. 7 in Nature . Postdoctoral scholar Wei Wei, Ph.D., is the lead author of the research.

Weight, nutrition and hunger: A complex relationship

The complicated web of interactions that govern when we get hungry, what and how much we eat, and how much we weigh is exceedingly difficult to untangle. Previous research in Long's laboratory uncovered a relationship between an "anti-hunger" molecule called lac-phe produced after vigorous exercise and the diabetes drug metformin that can cause moderate weight loss.

Conversely, mice genetically engineered to have low levels of taurine show muscle atrophy and a decreased capacity for exercise. But exactly how taurine has these effects has been unclear.

"Taurine does all sorts of stuff in our bodies, and is metabolized in many different ways," Long said. "It's a complicated soup."

One byproduct, or metabolite, of taurine is called N-acetyltaurine, which is formed when taurine and another molecule called acetate are combined. Levels of N-acetyltaurine in the body fluctuate in response to physiological changes—including endurance exercise and diet—that affect taurine and acetate levels.

As they were exploring taurine metabolism and its relationship to body weight, Wei and Long identified an enzyme called PTER, for phosphotriesterase-related, that converts N-acetyltaurine back into taurine. (Many metabolic pathways can run both forward and backward—a molecular seesaw that allows the body to respond nimbly to changes in diet, exercise and other variables.)

"Despite this genetic association, no one really knew what PTER did or why it was linked to body mass index in humans," Long said. "It was an orphan gene that encoded an orphan enzyme. Now we know that PTER breaks down, or hydrolyzes, N-acetyltaurine."

Teasing out molecular effects

When they were fed a diet high in fat, and given taurine in their drinking water, the mice without PTER ate and weighed significantly less than the control animals after eight weeks. The difference in body weight was due entirely to a reduction of fat mass in the knockout animals, the researchers found.

Further studies showed that the PTER pathway is independent of the pathway used by the GLP1 receptor agonists, such as Ozempic, currently on the market.

"This is a complicated interaction of genetics and diet that can regulate the body weight of these animals," Long said. "This is a fundamental advance in understanding how we eat affects our weight and our bodies."

Interestingly, it's not clear how N-acetyltaurine is made. It is possible that the gut microbiome plays a role. The researchers found that mice treated with antibiotics for one week to kill off much of their gut bacteria had 30% less N-acetyltaurine circulating in their bodies than before treatment.

"This possible role of the gut microbiome is interesting in the context of research into the rational manipulation of our intestinal bacteria for health," Long said. "Perhaps we could one day have probiotic or dietary interventions that promote the formation of N-acetyltaurine to reduce body weight. But much more work needs to be done."

Long and his colleagues are continuing their studies of PTER and taurine metabolites in people. The task is daunting but exciting.

"All of the stuff we eat, and we eat a lot of stuff, can interact with our bodies at a molecular and genetic level," Long said. "It's not a simple code. But we're starting to understand these intersecting pathways at a much more granular level than ever before."

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Genetics of obesity in humans: a clinical review.

1. Introduction

2. obesity-related genes and defects, 2.1. leptin, 2.2. proopiomelanocortin (pomc) deficiency, 2.3. melanocortin-4 receptor, 2.4. fto (fat mass and obesity associated gene), 2.5. chromosomal defects and obesity, 3. obesity-related syndromes, 3.1. prader–willi syndrome, 3.2. alstrom syndrome, 3.3. fragile x syndrome (fxs), 3.4. down syndrome, 3.5. bardet–biedl syndrome, 3.6. albright hereditary osteodystrophy, 3.7. wagr syndrome, 3.8. cohen syndrome, 3.9. smith–magenis syndrome, 3.10. kallmann syndrome, 4. management of genetic obesity, author contributions, informed consent statement, data availability statement, conflicts of interest.

Kaur, Y.; de Souza, R.J.; Gibson, W.T.; Meyre, D. A systematic review of genetic syndromes with obesity. Obes. Rev. 2017 , 18 , 603–634. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Purnell, J.Q. Definitions, Classification, and Epidemiology of Obesity. In Endotext ; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dhatariya, K., Dungan, K., Hershman, J.M., Hofland, J., Kalra, S., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2000. [ Google Scholar ]
Wardle, J.; Carnell, S.; Haworth, C.M.; Plomin, R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am. J. Clin. Nutr. 2008 , 87 , 398–404. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Singh, R.K.; Kumar, P.; Mahalingam, K. Molecular genetics of human obesity: A comprehensive review. Comptes Rendus Biol. 2017 , 340 , 87–108. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Duis, J.; Butler, M.G. Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans. Adv. Biol. 2022 , e2101154. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Butler, M.G. Single Gene and Syndromic Causes of Obesity: Illustrative Examples. Prog. Mol. Biol. Transl. Sci. 2016 , 140 , 1–45. [ Google Scholar ]
Farooqi, I.S. Genetic and hereditary aspects of childhood obesity. Best Pract. Res. Clin. Endocrinol. Metab. 2005 , 19 , 359–374. [ Google Scholar ] [ CrossRef ]
Xia, Q.; Grant, S.F. The genetics of human obesity. Ann. N. Y. Acad. Sci. 2013 , 1281 , 178–190. [ Google Scholar ] [ CrossRef ]
Choquet, H.; Meyre, D. Genetics of Obesity: What have we Learned? Curr. Genom. 2011 , 12 , 169–179. [ Google Scholar ] [ CrossRef ]
Lyon, H.N.; Hirschhorn, J.N. Genetics of common forms of obesity: A brief overview. Am. J. Clin. Nutr. 2005 , 82 (Suppl. S1), 215S–217S. [ Google Scholar ] [ CrossRef ]
Dietrich, J.; Lovell, S.; Veatch, O.J.; Butler, M.G. PHIP gene variants with protein modeling, interactions, and clinical phenotypes. Am. J. Med. Genet. Part A 2022 , 188 , 579–589. [ Google Scholar ] [ CrossRef ]
Friedman, J.M.; Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 1998 , 395 , 763–770. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Vohra, M.S.; Benchoula, K.; Serpell, C.J.; Hwa, W.E. AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity. Eur. J. Pharmacol. 2022 , 915 , 174611. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Franks, P.W.; Brage, S.; Luan, J.; Ekelund, U.; Rahman, M.; Farooqi, I.S.; Halsall, I.; O’Rahilly, S.; Wareham, N.J. Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity. Obes. Res. 2005 , 13 , 1476–1484. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Krude, H.; Gruters, A. Implications of proopiomelanocortin (POMC) mutations in humans: The POMC deficiency syndrome. Trends Endocrinol. Metab. 2000 , 11 , 15–22. [ Google Scholar ] [ CrossRef ]
Hilado, M.A.; Randhawa, R.S. A novel mutation in the proopiomelanocortin (POMC) gene of a Hispanic child: Metformin treatment shows a beneficial impact on the body mass index. J. Pediatr. Endocrinol. Metab. 2018 , 31 , 815–819. [ Google Scholar ] [ CrossRef ]
Gregoric, N.; Groselj, U.; Bratina, N.; Debeljak, M.; Zerjav Tansek, M.; Suput Omladic, J.; Kovac, J.; Battelino, T.; Kotnik, P.; Avbelj Stefanija, M. Two Cases With an Early Presented Proopiomelanocortin Deficiency-A Long-Term Follow-Up and Systematic Literature Review. Front. Endocrinol. 2021 , 12 , 689387. [ Google Scholar ] [ CrossRef ]
Yeo, G.S.; Farooqi, I.S.; Aminian, S.; Halsall, D.J.; Stanhope, R.G.; O’Rahilly, S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 1998 , 20 , 111–112. [ Google Scholar ] [ CrossRef ]
Tao, Y.X. The melanocortin-4 receptor: Physiology, pharmacology, and pathophysiology. Endocr. Rev. 2010 , 31 , 506–543. [ Google Scholar ] [ CrossRef ]
Frayling, T.M.; Timpson, N.J.; Weedon, M.N.; Zeggini, E.; Freathy, R.M.; Lindgren, C.M.; Perry, J.R.; Elliott, K.S.; Lango, H.; Rayner, N.W.; et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007 , 316 , 889–894. [ Google Scholar ] [ CrossRef ]
Scuteri, A.; Sanna, S.; Chen, W.M.; Uda, M.; Albai, G.; Strait, J.; Najjar, S.; Nagaraja, R.; Orru, M.; Usala, G.; et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007 , 3 , e115. [ Google Scholar ] [ CrossRef ]
Dina, C.; Meyre, D.; Gallina, S.; Durand, E.; Korner, A.; Jacobson, P.; Carlsson, L.M.; Kiess, W.; Vatin, V.; Lecoeur, C.; et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 2007 , 39 , 724–726. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cho, Y.S.; Go, M.J.; Kim, Y.J.; Heo, J.Y.; Oh, J.H.; Ban, H.J.; Yoon, D.; Lee, M.H.; Kim, D.J.; Park, M.; et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 2009 , 41 , 527–534. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wen, W.; Cho, Y.S.; Zheng, W.; Dorajoo, R.; Kato, N.; Qi, L.; Chen, C.H.; Delahanty, R.J.; Okada, Y.; Tabara, Y.; et al. Meta-analysis identifies common variants associated with body mass index in east Asians. Nat. Genet. 2012 , 44 , 307–311. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Okada, Y.; Kubo, M.; Ohmiya, H.; Takahashi, A.; Kumasaka, N.; Hosono, N.; Maeda, S.; Wen, W.; Dorajoo, R.; Go, M.J.; et al. Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat. Genet. 2012 , 44 , 302–306. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kalantari, N.; Keshavarz Mohammadi, N.; Izadi, P.; Gholamalizadeh, M.; Doaei, S.; Eini-Zinab, H.; Salonurmi, T.; Rafieifar, S.; Janipoor, R.; Azizi Tabesh, G. A complete linkage disequilibrium in a haplotype of three SNPs in Fat Mass and Obesity associated (FTO) gene was strongly associated with anthropometric indices after controlling for calorie intake and physical activity. BMC Med. Genet. 2018 , 19 , 146. [ Google Scholar ] [ CrossRef ]
Loos, R.J.F.; Yeo, G.S.H. The genetics of obesity: From discovery to biology. Nat. Rev. Genet. 2022 , 23 , 120–133. [ Google Scholar ] [ CrossRef ]
Castro, G.V.; Latorre, A.F.S.; Korndorfer, F.P.; de Carlos Back, L.K.; Lofgren, S.E. The Impact of Variants in Four Genes: MC4R, FTO, PPARG and PPARGC1A in Overweight and Obesity in a Large Sample of the Brazilian Population. Biochem. Genet. 2021 , 59 , 1666–1679. [ Google Scholar ] [ CrossRef ]
Dastgheib, S.A.; Bahrami, R.; Setayesh, S.; Salari, S.; Mirjalili, S.R.; Noorishadkam, M.; Sadeghizadeh-Yazdi, J.; Akbarian, E.; Neamatzadeh, H. Evidence from a meta-analysis for association of MC4R rs17782313 and FTO rs9939609 polymorphisms with susceptibility to obesity in children. Diabetes Metab. Syndr. 2021 , 15 , 102234. [ Google Scholar ] [ CrossRef ]
Resende, C.M.M.; Silva, H.; Campello, C.P.; Ferraz, L.A.A.; de Lima, E.L.S.; Beserra, M.A.; Muniz, M.T.C.; da Silva, L.M.P. Polymorphisms on rs9939609 FTO and rs17782313 MC4R genes in children and adolescent obesity: A systematic review. Nutrition 2021 , 91–92 , 111474. [ Google Scholar ] [ CrossRef ]
Dumesic, D.A.; Oberfield, S.E.; Stener-Victorin, E.; Marshall, J.C.; Laven, J.S.; Legro, R.S. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr. Rev. 2015 , 36 , 487–525. [ Google Scholar ] [ CrossRef ]
Glueck, C.J.; Goldenberg, N. Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics. Metab. Clin. Exp. 2019 , 92 , 108–120. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ewens, K.G.; Jones, M.R.; Ankener, W.; Stewart, D.R.; Urbanek, M.; Dunaif, A.; Legro, R.S.; Chua, A.; Azziz, R.; Spielman, R.S.; et al. FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS ONE 2011 , 6 , e16390. [ Google Scholar ] [ CrossRef ]
Tu, X.; Yu, C.; Gao, M.; Zhang, Y.; Zhang, Z.; He, Y.; Yao, L.; Du, J.; Sun, Y.; Sun, Z. LEPR gene polymorphism and plasma soluble leptin receptor levels are associated with polycystic ovary syndrome in Han Chinese women. Pers. Med. 2017 , 14 , 299–307. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Dasouki, M.J.; Youngs, E.L.; Hovanes, K. Structural Chromosome Abnormalities Associated with Obesity: Report of Four New subjects and Review of Literature. Curr. Genom. 2011 , 12 , 190–203. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cheon, C.K. Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome. Ann. Pediatr. Endocrinol. Metab. 2016 , 21 , 126–135. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Bellad, A.; Bandari, A.K.; Pandey, A.; Girimaji, S.C.; Muthusamy, B. A Novel Missense Variant in PHF6 Gene Causing Borjeson-Forssman-Lehman Syndrome. J. Mol. Neurosci. 2020 , 70 , 1403–1409. [ Google Scholar ] [ CrossRef ]
Hidestrand, P.; Vasconez, H.; Cottrill, C. Carpenter syndrome. J. Craniofac. Surg. 2009 , 20 , 254–256. [ Google Scholar ] [ CrossRef ]
Gupta, D.; Goyal, S. Cornelia de-Lange syndrome. J. Indian Soc. Pedod. Prev. Dent. 2005 , 23 , 38–41. [ Google Scholar ] [ CrossRef ]
Raible, S.E.; Mehta, D.; Bettale, C.; Fiordaliso, S.; Kaur, M.; Medne, L.; Rio, M.; Haan, E.; White, S.M.; Cusmano-Ozog, K.; et al. Clinical and molecular spectrum of CHOPS syndrome. Am. J. Med. Genet. Part A 2019 , 179 , 1126–1138. [ Google Scholar ] [ CrossRef ]
Abidi, F.E.; Cardoso, C.; Lossi, A.M.; Lowry, R.B.; Depetris, D.; Mattei, M.G.; Lubs, H.A.; Stevenson, R.E.; Fontes, M.; Chudley, A.E.; et al. Mutation in the 5’ alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. Eur. J. Hum. Genet. 2005 , 13 , 176–183. [ Google Scholar ] [ CrossRef ]
Rogers, R.C.; Abidi, F.E. Coffin-Lowry Syndrome. In GeneReviews((R)) ; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993. [ Google Scholar ]
Kleefstra, T.; de Leeuw, N. Kleefstra, T.; de Leeuw, N. Kleefstra Syndrome. In GeneReviews((R)) ; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993. [ Google Scholar ]
Milani, D.; Manzoni, F.M.; Pezzani, L.; Ajmone, P.; Gervasini, C.; Menni, F.; Esposito, S. Rubinstein-Taybi syndrome: Clinical features, genetic basis, diagnosis, and management. Ital. J. Pediatr. 2015 , 41 , 4. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
Kagami, M.; Nagasaki, K.; Kosaki, R.; Horikawa, R.; Naiki, Y.; Saitoh, S.; Tajima, T.; Yorifuji, T.; Numakura, C.; Mizuno, S.; et al. Temple syndrome: Comprehensive molecular and clinical findings in 32 Japanese patients. Genet. Med. 2017 , 19 , 1356–1366. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Yearwood, E.L.; McCulloch, M.R.; Tucker, M.L.; Riley, J.B. Care of the patient with Prader-Willi syndrome. Medsurg. Nurs. 2011 , 20 , 113–122. [ Google Scholar ] [ PubMed ]
Cassidy, S.B.; Driscoll, D.J. Prader-Willi syndrome. Eur. J. Hum. Genet. EJHG 2009 , 17 , 3–13. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Bittel, D.C.; Butler, M.G. Prader-Willi syndrome: Clinical genetics, cytogenetics and molecular biology. Expert Rev. Mol. Med. 2005 , 7 , 1–20. [ Google Scholar ] [ CrossRef ]
Gardner, R.M.; Sutherland, G.R.; Shaffer, L.G. Chromosome Abnormalities and Genetic Counseling , 4th ed.; Oxford University Press: New York, NY, USA, 2012. [ Google Scholar ]
Bachere, N.; Diene, G.; Delagnes, V.; Molinas, C.; Moulin, P.; Tauber, M. Early diagnosis and multidisciplinary care reduce the hospitalization time and duration of tube feeding and prevent early obesity in PWS infants. Horm. Res. 2008 , 69 , 45–52. [ Google Scholar ] [ CrossRef ]
Butler, J.V.; Whittington, J.E.; Holland, A.J.; McAllister, C.J.; Goldstone, A.P. The transition between the phenotypes of Prader-Willi syndrome during infancy and early childhood. Dev. Med. Child Neurol. 2010 , 52 , e88–e93. [ Google Scholar ] [ CrossRef ]
Oldzej, J.; Manazir, J.; Gold, J.A.; Mahmoud, R.; Osann, K.; Flodman, P.; Cassidy, S.B.; Kimonis, V.E. Molecular subtype and growth hormone effects on dysmorphology in Prader-Willi syndrome. Am. J. Med. Genet. Part A 2020 , 182 , 169–175. [ Google Scholar ] [ CrossRef ]
Mahmoud, R.; Leonenko, A.; Butler, M.G.; Flodman, P.; Gold, J.A.; Miller, J.L.; Roof, E.; Dykens, E.; Driscoll, D.J.; Kimonis, V. Influence of molecular classes and growth hormone treatment on growth and dysmorphology in Prader-Willi syndrome: A multicenter study. Clin. Genet. 2021 , 100 , 29–39. [ Google Scholar ] [ CrossRef ]
Miller, J.L.; Lynn, C.H.; Driscoll, D.C.; Goldstone, A.P.; Gold, J.A.; Kimonis, V.; Dykens, E.; Butler, M.G.; Shuster, J.J.; Driscoll, D.J. Nutritional phases in Prader-Willi syndrome. Am. J. Med. Genet. Part A 2011 , 155 , 1040–1049. [ Google Scholar ] [ CrossRef ]
Bereket, A.; Atay, Z. Current status of childhood obesity and its associated morbidities in Turkey. J. Clin. Res. Pediatr. Endocrinol. 2012 , 4 , 1–7. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Brambilla, P.; Crino, A.; Bedogni, G.; Bosio, L.; Cappa, M.; Corrias, A.; Delvecchio, M.; Di Candia, S.; Gargantini, L.; Grechi, E.; et al. Metabolic syndrome in children with Prader-Willi syndrome: The effect of obesity. Nutr. Metab. Cardiovasc. Dis. NMCD 2011 , 21 , 269–276. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Miller, J.L.; Goldstone, A.P.; Couch, J.A.; Shuster, J.; He, G.; Driscoll, D.J.; Liu, Y.; Schmalfuss, I.M. Pituitary abnormalities in Prader-Willi syndrome and early onset morbid obesity. Am. J. Med. Genet. Part A 2008 , 146 , 570–577. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Butler, J.V.; Whittington, J.E.; Holland, A.J.; Boer, H.; Clarke, D.; Webb, T. Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: A population-based study. Dev. Med. Child Neurol. 2002 , 44 , 248–255. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Li, G.; Vega, R.; Nelms, K.; Gekakis, N.; Goodnow, C.; McNamara, P.; Wu, H.; Hong, N.A.; Glynne, R. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet. 2007 , 3 , e8. [ Google Scholar ] [ CrossRef ]
Choudhury, A.R.; Munonye, I.; Sanu, K.P.; Islam, N.; Gadaga, C. A review of Alstrom syndrome: A rare monogenic ciliopathy. Intractable Rare Dis. Res. 2021 , 10 , 257–262. [ Google Scholar ] [ CrossRef ]
Hunter, J.E.; Berry-Kravis, E.; Hipp, H.; Todd, P.K. FMR1 Disorders. In GeneReviews((R)) ; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993. [ Google Scholar ]
Gantois, I.; Popic, J.; Khoutorsky, A.; Sonenberg, N. Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders. Annu. Rev. Med. 2019 , 70 , 167–181. [ Google Scholar ] [ CrossRef ]
Nowicki, S.T.; Tassone, F.; Ono, M.Y.; Ferranti, J.; Croquette, M.F.; Goodlin-Jones, B.; Hagerman, R.J. The Prader-Willi phenotype of fragile X syndrome. J. Dev. Behav. Pediatr. JDBP 2007 , 28 , 133–138. [ Google Scholar ] [ CrossRef ]
Raspa, M.; Bailey, D.B.; Bishop, E.; Holiday, D.; Olmsted, M. Obesity, food selectivity, and physical activity in individuals with fragile X syndrome. Am. J. Intellect. Dev. Disabil. 2010 , 115 , 482–495. [ Google Scholar ] [ CrossRef ]
Kidd, S.A.; Lachiewicz, A.; Barbouth, D.; Blitz, R.K.; Delahunty, C.; McBrien, D.; Visootsak, J.; Berry-Kravis, E. Fragile X syndrome: A review of associated medical problems. Pediatrics 2014 , 134 , 995–1005. [ Google Scholar ] [ CrossRef ]
Choo, T.H.; Xu, Q.; Budimirovic, D.; Lozano, R.; Esler, A.N.; Frye, R.E.; Andrews, H.; Velinov, M. Height and BMI in fragile X syndrome: A longitudinal assessment. Obesity 2022 , 30 , 743–750. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Presson, A.P.; Partyka, G.; Jensen, K.M.; Devine, O.J.; Rasmussen, S.A.; McCabe, L.L.; McCabe, E.R. Current estimate of Down Syndrome population prevalence in the United States. J. Pediatr. 2013 , 163 , 1163–1168. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Asim, A.; Kumar, A.; Muthuswamy, S.; Jain, S.; Agarwal, S. Down syndrome: An insight of the disease. J. Biomed. Sci. 2015 , 22 , 41. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hendrix, C.G.; Prins, M.R.; Dekkers, H. Developmental coordination disorder and overweight and obesity in children: A systematic review. Obes. Rev. 2014 , 15 , 408–423. [ Google Scholar ] [ CrossRef ]
Liou, T.H.; Pi-Sunyer, F.X.; Laferrere, B. Physical disability and obesity. Nutr. Rev. 2005 , 63 , 321–331. [ Google Scholar ] [ CrossRef ]
Maiano, C.; Normand, C.L.; Aime, A.; Begarie, J. Lifestyle interventions targeting changes in body weight and composition among youth with an intellectual disability: A systematic review. Res. Dev. Disabil. 2014 , 35 , 1914–1926. [ Google Scholar ] [ CrossRef ]
Magge, S.N.; O’Neill, K.L.; Shults, J.; Stallings, V.A.; Stettler, N. Leptin levels among prepubertal children with Down syndrome compared with their siblings. J. Pediatr. 2008 , 152 , 321–326. [ Google Scholar ] [ CrossRef ]
Hill, D.L.; Parks, E.P.; Zemel, B.S.; Shults, J.; Stallings, V.A.; Stettler, N. Resting energy expenditure and adiposity accretion among children with Down syndrome: A 3-year prospective study. Eur. J. Clin. Nutr. 2013 , 67 , 1087–1091. [ Google Scholar ] [ CrossRef ]
Nordstrom, M.; Retterstol, K.; Hope, S.; Kolset, S.O. Nutritional challenges in children and adolescents with Down syndrome. Lancet Child Adolesc. Health 2020 , 4 , 455–464. [ Google Scholar ] [ CrossRef ]
Fructuoso, M.; Rachdi, L.; Philippe, E.; Denis, R.G.; Magnan, C.; Le Stunff, H.; Janel, N.; Dierssen, M. Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome. Free Radic. Biol. Med. 2018 , 114 , 122–130. [ Google Scholar ] [ CrossRef ]
Florea, L.; Caba, L.; Gorduza, E.V. Bardet-Biedl Syndrome-Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype-Phenotype Correlations. Genes 2021 , 12 , 1353. [ Google Scholar ] [ CrossRef ]
Mantovani, G.; Elli, F.M. Inactivating PTH/PTHrP Signaling Disorders. Front. Horm. Res. 2019 , 51 , 147–159. [ Google Scholar ] [ PubMed ]
Thiele, S.; de Sanctis, L.; Werner, R.; Grotzinger, J.; Aydin, C.; Juppner, H.; Bastepe, M.; Hiort, O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum. Mutat. 2011 , 32 , 653–660. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Butler, M.G. Imprinting disorders in humans: A review. Curr. Opin. Pediatr. 2020 , 32 , 719–729. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ong, K.K.; Amin, R.; Dunger, D.B. Pseudohypoparathyroidism--another monogenic obesity syndrome. Clin. Endocrinol. 2000 , 52 , 389–391. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Delaval, K.; Wagschal, A.; Feil, R. Epigenetic deregulation of imprinting in congenital diseases of aberrant growth. BioEssays 2006 , 28 , 453–459. [ Google Scholar ] [ CrossRef ]
Fischbach, B.V.; Trout, K.L.; Lewis, J.; Luis, C.A.; Sika, M. WAGR syndrome: A clinical review of 54 cases. Pediatrics 2005 , 116 , 984–988. [ Google Scholar ] [ CrossRef ]
Breslow, N.E.; Norris, R.; Norkool, P.A.; Kang, T.; Beckwith, J.B.; Perlman, E.J.; Ritchey, M.L.; Green, D.M.; Nichols, K.E.; National Wilms Tumor Study Group. Characteristics and outcomes of children with the Wilms tumor-Aniridia syndrome: A report from the National Wilms Tumor Study Group. J. Clin. Oncol. 2003 , 21 , 4579–4585. [ Google Scholar ] [ CrossRef ]
Gul, D.; Ogur, G.; Tunca, Y.; Ozcan, O. Third case of WAGR syndrome with severe obesity and constitutional deletion of chromosome (11)(p12p14). Am. J. Med. Genet. 2002 , 107 , 70–71. [ Google Scholar ] [ CrossRef ]
Marlin, S.; Couet, D.; Lacombe, D.; Cessans, C.; Bonneau, D. Obesity: A new feature of WAGR (del 11p) syndrome. Clin. Dysmorphol. 1994 , 3 , 255–257. [ Google Scholar ] [ CrossRef ]
Tiberio, G.; Digilio, M.C.; Giannotti, A. Obesity and WAGR syndrome. Clin. Dysmorphol. 2000 , 9 , 63–64. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Han, J.C.; Liu, Q.R.; Jones, M.; Levinn, R.L.; Menzie, C.M.; Jefferson-George, K.S.; Adler-Wailes, D.C.; Sanford, E.L.; Lacbawan, F.L.; Uhl, G.R.; et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N. Engl. J. Med. 2008 , 359 , 918–927. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rodrigues, J.M.; Fernandes, H.D.; Caruthers, C.; Braddock, S.R.; Knutsen, A.P. Cohen Syndrome: Review of the Literature. Cureus 2018 , 10 , e3330. [ Google Scholar ] [ CrossRef ]
Wang, H.; Falk, M.J.; Wensel, C.; Traboulsi, E.I. Cohen Syndrome. In GeneReviews((R)) ; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993. [ Google Scholar ]
Limoge, F.; Faivre, L.; Gautier, T.; Petit, J.M.; Gautier, E.; Masson, D.; Jego, G.; El Chehadeh-Djebbar, S.; Marle, N.; Carmignac, V.; et al. Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome. Hum. Mol. Genet. 2015 , 24 , 6603–6613. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Smith, A.C.M.; Boyd, K.E.; Brennan, C.; Charles, J.; Elsea, S.H.; Finucane, B.M.; Foster, R.; Gropman, A.; Girirajan, S.; Haas-Givler, B. Smith-Magenis Syndrome. In GeneReviews((R)) ; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993. [ Google Scholar ]
Stamou, M.I.; Georgopoulos, N.A. Kallmann syndrome: Phenotype and genotype of hypogonadotropic hypogonadism. Metabolism 2018 , 86 , 124–134. [ Google Scholar ] [ CrossRef ]
Markham, A. Setmelanotide: First Approval. Drugs 2021 , 81 , 397–403. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Farooqi, I.S.; Matarese, G.; Lord, G.M.; Keogh, J.M.; Lawrence, E.; Agwu, C.; Sanna, V.; Jebb, S.A.; Perna, F.; Fontana, S.; et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Investig. 2002 , 110 , 1093–1103. [ Google Scholar ] [ CrossRef ]
Lindgren, A.C.; Hagenas, L.; Muller, J.; Blichfeldt, S.; Rosenborg, M.; Brismar, T.; Ritzen, E.M. Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: A preliminary report. The Swedish National Growth Hormone Advisory Group. Acta Paediatr. 1997 , 423 , 60–62. [ Google Scholar ] [ CrossRef ]
Lindgren, A.C.; Hagenas, L.; Muller, J.; Blichfeldt, S.; Rosenborg, M.; Brismar, T.; Ritzen, E.M. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably. Acta Paediatr. 1998 , 87 , 28–31. [ Google Scholar ] [ CrossRef ]
Eiholzer, U.; Gisin, R.; Weinmann, C.; Kriemler, S.; Steinert, H.; Torresani, T.; Zachmann, M.; Prader, A. Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance. Eur. J. Pediatr. 1998 , 157 , 368–377. [ Google Scholar ] [ CrossRef ]
Whitman, B.Y.; Myers, S.; Carrel, A.; Allen, D. The behavioral impact of growth hormone treatment for children and adolescents with Prader-Willi syndrome: A 2-year, controlled study. Pediatrics 2002 , 109 , E35. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
Goldstone, A.P.; Holland, A.J.; Hauffa, B.P.; Hokken-Koelega, A.C.; Tauber, M.; Speakers Contributors at the Second Expert Meeting of the Comprehensive Care of Patients with PWS. Recommendations for the diagnosis and management of Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 2008 , 93 , 4183–4197. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Festen, D.A.; de Lind van Wijngaarden, R.; van Eekelen, M.; Otten, B.J.; Wit, J.M.; Duivenvoorden, H.J.; Hokken-Koelega, A.C. Randomized controlled GH trial: Effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome. Clin. Endocrinol. 2008 , 69 , 443–451. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Medscape. FDA Approves First Drug to Treat Children with Prader-Willi Syndrome Medscape Medical News [Online], 2000. Available online: http://www.medscape.com/viewarticle/411964 (accessed on 14 May 2010).
Butler, M.G.; Smith, B.K.; Lee, J.; Gibson, C.; Schmoll, C.; Moore, W.V.; Donnelly, J.E. Effects of growth hormone treatment in adults with Prader-Willi syndrome. Growth Horm. IGF Res. 2013 , 23 , 81–87. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]

Click here to enlarge figure

Gene	Mode of Inheritance	Clinical Features	Reference
PHF6	X-linked	Developmental delay Obesity Seizure Skeletal anomalies Large ears Hypogonadism Gynecomastia Distinctive facial features	[ ]
RAB23	Autosomal recessive	Peculiar facies Brachydactyly of the hands Syndactyly Preaxial polydactyly Congenital heart defects Intellectual disability Hypogenitalism Obesity	[ ]
NIPBL-CdLS, RAD21-CdLS, SMC3-CdLS, BRD4-CdLS,HDAC8-CdLS, SMC1A-CdLS	Autosomal dominant X-linked	Microcephaly Synophrys Short nasal bridge Long and/or smooth philtrum Highly arched palate with or without cleft palate Behavioral problems Micrognathia Hearing loss Tendency to overweight	[ ]
AFF4	Autosomal dominant	Cognitive impairment Coarse facies Heart defects Obesity Short stature, and Skeletal dysplasia.	[ ]
ATRX	X-linked	Intellectual disability Short stature Macrosomia Obesity Hypogonadism Distinctive facial features	[ ]
RPS6KA3	X-linked	Severe intellectual disability Kyphoscoliosis, Behavioral problems, Progressive spasticity, Paraplegia, Sleep apnea Stroke	[ ]
EHMT1	9q34.3 deletion Autosomal dominant	Intellectual disability Obesity Hypotonia Congenital heart defects Genitourinary anomalies Seizures Distinctive facial features	[ ]
CREBBP, EP300	Autosomal dominant	Distinctive facial features, Broad thumbs and halluces Short stature Intellectual disability Obesity in childhood or adolescence	[ ]
Aberrations at the 14q32.2 imprinted region	Maternal disomy 14	Feeding difficulties Hypotonia Motor developmental delay Childhood-onset central obesity Mild facial dysmorphism	[ ]

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Mahmoud, R.; Kimonis, V.; Butler, M.G. Genetics of Obesity in Humans: A Clinical Review. Int. J. Mol. Sci. 2022 , 23 , 11005. https://doi.org/10.3390/ijms231911005

Mahmoud R, Kimonis V, Butler MG. Genetics of Obesity in Humans: A Clinical Review. International Journal of Molecular Sciences . 2022; 23(19):11005. https://doi.org/10.3390/ijms231911005

Mahmoud, Ranim, Virginia Kimonis, and Merlin G. Butler. 2022. "Genetics of Obesity in Humans: A Clinical Review" International Journal of Molecular Sciences 23, no. 19: 11005. https://doi.org/10.3390/ijms231911005

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New study links obesity to bacterium Megamonas

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A recent study published in Cell Host & Microbe identifies a potential obesity-linked bacterium, Megamonas , from a large-scale cohort of obese individuals in China. This research suggests potential strategies for future obesity management by illustrating how the bacterium degrades intestinal myo-inositol, enhances lipid absorption, and contributes to obesity.

The study is jointly conducted by Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, BGI Research, and BGI Genomics Institute of Intelligent Medical Research (IIMR).

Through a large-scale study of intestinal metagenome and host genome in obese Chinese, this research reveals a strong link between gut Megamonas and obesity." Dr. Yang Fangming, co-first author from BGI Genomics

Dr. Yang adds, "The research uncovers the mechanism by which Megamonas induces obesity, providing a new target bacterium for the diagnosis and treatment of obesity."

The researchers performed metagenomic sequencing on fecal samples from 1,005 individuals, including 631 obese individuals and 374 normal-weight individuals, and conducted whole-genome sequencing (WGS) on 814 of these participants. They reveal a strong link between Megamonas and obesity-;the combination of Megamonas and host genetic risk factors significantly increased the likelihood of obesity.

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Research shows our bodies go through rapid changes in our 40s and our 60s

For many people, reaching their mid-40s may bring unpleasant signs the body isn’t working as well as it once did. Injuries seem to happen more frequently. Muscles may feel weaker.

A new study, published Wednesday in Nature Aging , shows what may be causing the physical decline. Researchers have found that molecules and microorganisms both inside and outside our bodies are going through dramatic changes, first at about age 44 and then again when we hit 60. Those alterations may be causing significant differences in cardiovascular health and immune function.

The findings come from Stanford scientists who analyzed blood and other biological samples of 108 volunteers ages 25 to 75, who continued to donate samples for several years.

“While it’s obvious that you’re aging throughout your entire life, there are two big periods where things really shift,” said the study’s senior author, Michael Snyder, a professor of genetics and director of the Center for Genomics and Personalized Medicine at Stanford Medicine. For example, “there’s a big shift in the metabolism of lipids when people are in their 40s and in the metabolism of carbohydrates when people are in their 60s.”

Lipids are fatty substances, including LDL, HDL and triglycerides, that perform a host of functions in the body, but they can be harmful if they build up in the blood.

The scientists tracked many kinds of molecules in the samples, including RNA and proteins, as well as the participants’ microbiomes.

The metabolic changes the researchers discovered indicate not that people in their 40s are burning calories more slowly but rather that the body is breaking food down differently. The scientists aren’t sure exactly what impact those changes have on health.

Previous research showed that resting energy use, or metabolic rate , didn’t change from ages 20 to 60. The new study’s findings don't contradict that.

The changes in metabolism affect how the body reacts to alcohol or caffeine, although the health consequences aren’t yet clear. In the case of caffeine, it may result in higher sensitivity.

It’s also not known yet whether the shifts could be linked to lifestyle or behavioral factors. For example, the changes in alcohol metabolism might be because people are drinking more in their mid-40s, Snyder said.

For now, Snyder suggests people in their 40s keep a close eye on their lipids, especially LDL cholesterol.

“If they start going up, people might want to think about taking statins if that’s what their doctor recommends,” he said. Moreover, “knowing there’s a shift in the molecules that affect muscles and skin, you might want to warm up more before exercising so you don’t hurt yourself.”

Until we know better what those changes mean, the best way to deal with them would be to eat healthy foods and to exercise regularly, Snyder said.

Dr. Josef Coresh, founding director of the Optimal Aging Institute at the NYU Grossman School of Medicine, compared the new findings to the invention of the microscope.

“The beauty of this type of paper is the level of detail we can see in molecular changes,” said Coresh, a professor of medicine at the school. “But it will take time to sort out what individual changes mean and how we can tailor medications to those changes. We do know that the origins of many diseases happen in midlife when people are in their 40s, though the disease may occur decades later.”

The new study “is an important step forward,” said Dr. Lori Zeltser, a professor of pathology and cell biology at the Columbia University Vagelos College of Physicians and Surgeons. While we don’t know what the consequences of those metabolic changes are yet, “right now, we have to acknowledge that we metabolize food differently in our 40s, and that is something really new.”

The shifts the researchers found might help explain numerous age-related health changes, such as muscle loss, because “your body is breaking down food differently,” Zeltser said.

Linda Carroll is a regular health contributor to NBC News. She is coauthor of "The Concussion Crisis: Anatomy of a Silent Epidemic" and "Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings."

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Weight-loss drugs like wegovy may help stave off some cancers.

Yuki Noguchi

Obesity, Cancer, and GLP1s

GLP-1 drugs, like Wegovy and Ozempic, may not be good only for diabetes and weight-loss. They are also showing promise for preventing some cancers. UCG/Universal Images Group/Getty Images hide caption

Drugs like Ozempic, Wegovy and Zepbound have transformed treatment for obesity and diabetes. Now researchers are excited about their potential impact on other conditions, including addiction and sleep apnea — and even cancer.

Scientists see this class of drugs, called GLP-1 agonists, as a breakthrough because of how they act on the brain to regulate the body’s hormones, slow digestion, and tamp down hunger. And in several recent studies, they show early promise in preventing many common cancers — including breast, colon, liver, and ovarian — known to be driven by obesity and excess weight.

“It's a hopeful story, which is, frankly, what people need,” says Arif Kamal, an oncologist specializing in breast cancer as well as chief patient officer at the American Cancer Society.

Though research on GLP-1 drugs is still in its relative infancy, so far studies fairly consistently show their benefit in staving off certain cancers. One research letter published in JAMA Oncology last year, for example, suggests GLP-1 drugs might reduce the risk of colon cancer , even among people who are not overweight. A more recent analysis in JAMA Network Open suggests GLP-1s provide far more protection against cancer for diabetic patients than insulin treatments.

Another recent study presented at the American Society of Clinical Oncologists meeting in June, showed both bariatric surgery and GLP-1 medications dramatically reduce the risk of the 13 obesity-related cancers . Among those who had bariatric surgery, that risk declined by 22% over 10 years compared to those who received no treatment. But among those taking GLP1 medications, risk dropped by a whopping 39%.

“And I think a 39% risk reduction is one of the most impactful risk reductions we've ever really seen,” says Kamal.

GLP-1 agonist drugs were originally developed to treat diabetes nearly two decades ago. Over the past decade, regulators started approving them as treatments for weight loss – first as liraglutide, sold under the brand Saxenda and, more recently, in the form of semaglutide or tirzepatide, under brands like Wegovy and Zepbound.

When it comes to cancer prevention, scientists are finding the link between obesity in cancer is complex and intertwined; the obesity-related cancers are heavily concentrated among organs involved in digestion and metabolism, like the liver and pancreas, for example, as well as among gynecologic cancers, including breast and uterus. Reproductive organs are highly sensitive to the hormone estrogen, which plays a role in allowing cells to grow rapidly during pregnancy, for example.

But Kamal says there’s also an especially close relationship between estrogen and cancer. “What we do know is that estrogen in particular — and possibly some other hormones, but estrogen for sure — drives the growth of many cancers,” he says. And fat cells increase production of estrogen.

That means women today are increasingly susceptible to cancer. Historically, men faced a much higher risk of developing cancers — in large part because they were more likely to engage in high-risk behaviors like smoking or drinking, Kamal says. But in recent years, the high prevalence of obesity among both men and women is closing that gender gap.

Obesity is also likely the most significant driver behind increasing cancer rates among younger adults , he says, just as tobacco was in generations past.

“Unhealthy weight is the smoking of our generation,” Kamal says.

That’s why indications that GLP-1 drugs may help slash that risk is so significant.

What’s more, that ASCO study suggests that GLP-1 drugs have a notable impact on cancer risk, even when patients don’t lose a lot of weight as a result of taking them. In other words, the medications seem to act on a number of the body’s mechanisms to reduce vulnerabilities to cancer.

“We think the protective effects of GLP-1s are probably multifactorial,” says Cindy Lin, resident physician at Case Western Reserve and co-author of the June ASCO study. “Part of it is weight [loss], but other factors may be contributing as well — better glycemic controls, anti-inflammatory effects.”

More research is necessary and inevitable — especially studies looking at the newer weight-loss formulations of GLP-1 medications, says Benjamin Liu, another resident physician at Case Western and co-author of the ASCO study.

He says he’s encouraged by the data so far. “It's very exciting to have, especially since it's more of a noninvasive strategy compared to bariatric surgery, and a lot more patients will be open to it.”

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GENETIC AND EPIGENETIC CAUSES OF OBESITY

Vidhu v. thaker.

1 Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY

2 Harvard Medical School, Boston, MA

3 Division of Endocrinology, Boston Children’s Hospital, Boston, MA

Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. With the increasing access to high precision diagnostic tools for genetic investigations, numerous genes influencing the phenotype have been identified, especially in early onset severe obesity. This review summarizes the current knowledge on the known genetic causes of obesity and the available therapeutic options. Furthermore, we discuss the role and potential mechanism of epigenetic changes that may be involved as mediators of the environmental influences and that may provide future opportunities for intervention.

INTRODUCTION

The idea of innate biologic (“endogenous”) cause of obesity was first proposed by Von Noorden in 1907 1 . This concept of genetic cause for obesity has been investigated time and again since then 2 . The landmark studies of body fatness in 540 adopted Danish twins by Stunkard and colleagues showed that the weight of the adults was closer to their biological parents despite being reared in an adopted family. 3 Further, they examined the body mass index (BMI) of twins reared together and apart to conclude the heritability of about 70%. 4 Experimental studies of overfeeding in identical twins by Bouchard et al showed a remarkable correlation of weight gain within twin pairs, much higher than that between pairs. 5 The longitudinal follow-up of these subjects showed a similar correlation of initial weight loss and eventual rebound. 6 In a systematic review of twin studies, Silventoinen et al noted variable heritability of weight across lifetime with an overall effect between 45–90%. This meta-analysis of twin studies showed highest heritability in the early childhood, adolescence and adulthood. Additionally, they recognized the influence of genetics on obesity related behavior such as eating patterns and exercise. 7

Secular trends in obesity in children, adolescents 8 and adults 9 have shown an increase in obesity with urbanization, clearly indicating the role of the environment. But in any given environment, there is considerable individual variation in body weight and fat mass, suggesting that adiposity is influenced by complex interactions between genetic, developmental, behavioral, and environmental influences.

Modern genetic technology with precise definition of single nucleotide changes has advanced our understanding of the molecular mechanisms of weight regulation. Specifically, high throughput sequencing with whole exome, genome and targeted sequencing in individual subjects and cohorts of children with severe obesity has identified little known genetic aberrations. Besides providing insight into the pathophysiology of weight regulation, some of these etiologies hold the potential for treatment in selected individuals. Furthermore, studies in model organisms have elucidated epigenetic modifications that may play a role in weight gain. This review will address the identified genetic causes of obesity, and summarize the current literature on the epigenetic changes.

Genetic causes of obesity can be broadly classified into:

Monogenic causes: those caused by a single gene mutation, primarily located in the leptin- melanocortin pathway.
Syndromic obesity: severe obesity associated with other phenotypes such as neurodevelopmental abnormalities, and other organ/system malformations.
Polygenic obesity: caused by cumulative contribution of a large number of genes whose effect is amplified in a ‘weight gain promoting’ environment.

We will focus here on the first 2 categories.

CENTRAL REGULATORY PATHWAY

A basic overview of the central regulatory pathway of appetite regulation will facilitate the understanding of genetic mutations ( Figure 1 ). The central nervous system plays a vital role in regulating food intake through the brain-gut axis, with the hypothalamic leptin-melanocortin pathway as the key regulator of energy balance. 10 Signals are received from several tissues and organs, such as the gut: hormones like ghrelin, peptide YY (PYY), cholecystokinin (CCK), glucagon-like peptide (GLP-1) and mechanoreceptors measuring distention; by pancreas through insulin; and by adipokine hormones such as leptin and adiponectin. The hypothalamus integrates these signals and acts via downstream pathways to maintain energy balance. The leptin/melanocortin pathway is activated via the leptin (LEPR) and insulin receptors (INSR) located on the surface of the neurons of the arcuate nucleus. These signals are in-turn regulated by 2 sets of neurons in a feedback loop. The pro-opiomelanocortin and cocaine and amphetamine related transcript neurons (POMC/CART) regulate production of anorexogenic peptide POMC, while a separate set of neurons regulate production of orexogenic agouti-related peptide (AGRP) and neuropeptide-Y (NPY). 11 After post-translational processing with proconvertase 1 (PC1) and proconvertase 2 (PC2), POMC results in the production of a variety of peptides, such as α- β- and γ-melanocyte stimulating hormone (MSH) and β-endorphins. 12 AGRP and α-MSH compete for binding with the melanocortin-4 receptor (MC4R), which is highly expressed in the paraventricular nucleus (PVN) of the hypothalamus. Binding with α-MSH results in anorexigenic signals, while that with AGRP in orexogenic signals. 13 Signals from MC4R govern food intake via secondary effector neurons that lead to higher cortical centers, a process that involves brain-derived neurotrophic factor (BDNF) and neurotrophic tyrosine kinase receptor type 2 (NTRK2 coding for the receptor called tropomyosin-related kinase B, TrkB). Other regulators such as SIM1, have been found to modulate the effect of this pathway. Mutations in the various genes involved in this pathway have been identified to be causal for obesity.

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The integration of the various peripheral and central signals in the hypothalamus is critical to the weight regulation. Hormonal (ghrelin, leptin, insulin) and mechano- and baroreceptor signals are sensed by the receptors located in the arcuate nucleus of the hypothalamus. These result in the production of pro-opiomelanocortin (POMC, anorexogenic) or Agouti-related peptide (AgRP) or PYY (orexogenic), sensed by the melanocortin-4 receptor (MC4R) located predominantly in the paraventricular nucleus. Proconvertase-1 (PC1) and 2 (PC2) are required for processing of the prohormones into α-melanocyte stimulating hormone (α-MSH), and β-MSH, ligands for the MC4R. The downstream expression of MC4R is influenced by Single-minded homologue 1 (SIM1), Brain-derived neurotrophic factor (BDNF), possibly retinoic induced acid (RAI1, not shown), and mediated via Tyrosine kinase receptor (TrkB). Disruptions in the genes involved in this pathway have been shown to cause monogenic obesity in humans.

Image from: Mutch DM, Clément K. Unraveling the Genetics of Human Obesity. PLoS Genetics 2006, 2:12, e188 under Creative Commons License.

MONOGENIC OBESITY

Many of the genes identified for monogenic obesity disrupt the regulatory system of appetite and weight described above. Most mutations require 2 dysfunctional copies of the gene in homozygous or compound heterozygous form to manifest the phenotype. A summary of the individual causes of monogenic obesity can be found in Table 1 .

SINGLE GENES KNOWN TO BE INVOLVED WITH OBESITY

NAME	MIM	MODE of INHERITANCE	CHROMOSOMAL POSITION

Leptin	164160	AR	7q32.1
Leptin receptor	601007	AR	1p31.2
Proopiomelanocortin	176830	AR	2p23.2
Melanocortin 4 receptor	155541	AD/AR	18q21.32
Single-minded Drosophila Homologue-1	603128	AD	6q16.3
Nurotrophic Tyrosine Kinase Receptor Type 2	600456	AD	9q21.33
Kinase suppressor of Ras2	610737	AD	12q24.22-q24.23
Carboxypeptidase	114855	AD	4q32.3
Proconvertase 1	162150	AR	5q15
Brain Derived Neurotropic factor	113505	AD	11p14.1
SH2B adaptor protein	608937	AD	16p11.2
Tubby, Homogue of Mouse	601197	AR	11p15.4

AD= Autosomal dominant, AR = Autosomal recessive.

For detailed information and references, refer to Online Mendelian Inheritance in Man using the MIM number: https://www.omim.org

Leptin ( LEP ) mutations

Leptin is a type I cytokine mainly secreted by the adipocytes to signal the energy state of the body and exerts its function as a satiety signal in the hypothalamus. 14 , 15 Encoded by the LEP gene located on chromosome 7q31.3, it is synthesized as an immature 167-amino acid protein that forms a 146-amino acid mature protein after cleavage of the 21-amino-acid N-terminal peptide. 14

Congenital leptin deficiency follows a recessive mode of inheritance, and was first identified in two extremely obese first-degree cousins from a Pakistani family caused by a frameshift mutation (c.398 del G). 16 Since then ten other mutations in the leptin gene have been described. 17 – 27 The cardinal phenotypic manifestations are rapid weight gain after normal birth weight resulting in severe early onset obesity caused by intense hyperphagia. 28 In addition, some of these children have severe and possibly lethal bacterial infections due to defective T-cell immunity 29 and hypogonadotropic hypogonadism. 16 The children often have secondary adverse effects of severe obesity such as hyperinsulinemia, severe liver steatosis and dyslipidemia. The protein change can vary from early termination of the protein resulting in low to undetectable levels of the leptin hormone to the loss of biological activity with normal levels. 27

Although relatively rare, and mostly seen in consanguineous families, congenital leptin deficiency presents a unique opportunity for treatment with recombinant leptin that improves the adiposity, and restores gonadal and immune function. 27 , 30 The Food and Drug Administration has approved the use of Myalept (metreleptin) for the treatment of congenital leptin deficiency and generalized lipodystrophy. 31

Leptin Receptor ( LEPR ) mutations

Mutations in LEPR can cause phenotype similar to that of leptin deficiency, without low serum levels. 32 The use of next generation sequencing has facilitated the identification of LEPR mutations, with estimates of 2–3% in certain populations. 33 – 36 Co-existing growth hormone and thyroid function deficiency has also been described. 37 , 38 Unlike leptin deficiency, individuals with homozygous LEPR mutations are not amenable to treatment with recombinant leptin.

Pro-opio melanocortin ( POMC) mutations

Deficiency in the POMC protein results in the absence of cleavage products of ACTH, α-MSH and β-endorphins. 39 Due to the dual role of α-MSH in appetite regulation and pigmentation, the classic presentation is that of red hair and severe obesity. Adrenal insufficiency results from deficiency of ACTH. Early recognition of adrenal insufficiency and rapid glucocorticoid replacement therapy is important for treatment. Fewer than 10 patients have been described around the world. A few studies have also noted the presence of heterozygous POMC mutations in individuals with obesity, without adrenal insufficiency and other classic manifestations. 40 , 41 A new melanocortin-4 receptor agonist, Setmelanotide, has been shown to have therapeutic potential for POMC deficiency. 42

MC4R deficiency

The melanocortin receptor (MC4R) is a G-protein coupled, seven transmembrane receptor which is highly expressed in the hypothalamus, the region of the brain involved in appetite regulation. 43 Rodent studies indicate that the binding of MC4R with α-MSH, its high affinity ligand produced from POMC, inhibits feeding. 44 Subsequently, mutations in MC4R , both in dominant and recessive form, have been demonstrated as the most common cause of inherited early-onset obesity with prevalence between 0.5–6% in different populations. 45 – 49 Affected children demonstrate hyperphagia with food-seeking behavior in early childhood, are taller than their peers, may have higher blood pressure and advanced bone age, but are otherwise not dysmorphic. 45 Therapeutic perturbation of the MC4R to improve the satiety circuits is an active area of investigation, but not available for clinical use yet. 50 – 52

Proconvertase (PC1/2 ) deficiency

Proprotein convertase-1/2 are neuroendocrine convertase endoproteases that process large precursor proteins into mature bioactive products. 53 Absence of activity of PC1/PC2 results in adrenal, gonadotropic, somatotropic, and thyrotropic insufficiency, along with postprandial hypoglycemic malaise caused by lack of insulin processing, severe malabsorptive neonatal diarrhea and central diabetes insipidus, in addition to severe early onset obesity. 54 – 58 These enzymes are an attractive target for molecular intervention, although no therapies are available at the moment.

SIM1 deficiency

Single-minded homologue of drosophila ( SIM1 ) is a transcription factor located on chromosome 6q16 and is strongly expressed in the paraventricular nucleus of the hypothalamus, a critical regulator of appetite. 59 Deletions or heterozygous mutations in SIM1 have been associated with hyperphagia, food impulsivity, and neurobehavioral features such as impaired concentration, memory deficit, emotional lability or autism spectrum disorder. 60 , 61

NTRK2/BDNF mutations

These neurotrophins are a family of growth factors known to be involved in the development, maintenance and function of peripheral and central neurons. The neurotrophin receptor TrkB and its natural ligand, brain derived neurotrophic factor (BDNF), have been implicated in the regulation of food intake and body weight in animal studies. Heterozygous loss of function mutation in NTRK2 , that codes for TrkB was demonstrated in a Caucasian male with severe early onset obesity with no other syndromic features. 62 Individuals with deletions in BDNF gene as part of the WAGR syndrome (Wilms’ tumor, aniridia, genitourinary anomalies and mental retardatio) have early onset obesity 63 .

SH2B1 mutations

Src homology 2 B adapter protein ( SH2B1 ) is a positive regulator of leptin sensitivity. 64 Following the identification of its role in animal models, mutations in SH2B1 were noted in 5 children of mixed European descent with severe early onset obesity inherited from their overweight/obese parents. 65 The mutation carriers were noted to be hyperphagic, had reduced final adult height, hyperinsulinemia without diabetes, delayed speech and language, and aggressive behavior. Subsequent studies of additional variants in the gene have shown milder phenotypes indicating a variability in the presentation. 66

Other monogenic forms of obesity

With the increasing use of whole exome and genome testing, additional single gene defects causing obesity have been identified. Mutations in kinase suppressor of Ras 2 ( KSR2) , an intracellular scaffolding protein involved in multiple pathways causes hyperphagia in childhood, low heart rate, reduced metabolic rate and severe insulin resistance. 67 This mutation is of great interest, as metformin may be useful in decreasing the body weight and improving insulin sensitivity in these individuals. A homozygous frameshift mutation in the TUB (tubby-like protein) gene was identified in a proband who presented with obesity, decreased visual acuity and night blindness, and electrophysiological features of rod-cone dystrophy. 68 In another case, a severely obese female from a consanguineous Sudanese family with intellectual disability, type 2 diabetes, and hypogonadotrophic hypogonadism was found to have a homozygous truncating mutation in carboxypeptidase ( CPE ) gene. CPE is an enzyme involved in the processing of a number of neuropeptide and peptide hormones (akin to proconvertase). 69 Our group has demonstrated a novel truncating mutation in retinoic acid induced gene ( RAI1 ) in an individual with hypoventilation, hypothalamic dysfunction, developmental disability, autonomic dysfunction and severe obesity. 70 Mutations in RAI1 gene interfere with the BDNF expression in the hypothalamus in animals, thus interfering with the leptin-melanocortin signaling 71 .

SYNDROMIC OBESITY

The syndromic forms of obesity are often associated with phenotypes in addition to the early-onset severe obesity. This may be caused by change in a single gene or a larger chromosomal region encompassing several genes. Obesity is a feature of almost 100 syndromes; a little over half are not yet named, and 13.9% have more than one name. 72 The co-presenting phenotypes often include intellectual disability, dysmorphic facies, or organ-system specific abnormalities. The most frequent forms of syndromic obesity are Bardet Biedl and Prader Willi syndrome.

Bardet-Biedel Syndrome (BBS)

BBS is a rare autosomal recessive ciliopathy characterized by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. 73 The prevalence of BBS varies markedly between populations; from 1:160 000 in northern European populations to 1:13500 and 1:17 5000, respectively, in isolated communities in Kuwait and Newfoundland, where a higher level of consanguinity prevails. The phenotype evolves slowly through the first decade of life, and often the only manifestation seen at birth may be post-axial polydactyly, with or without other limb abnormalities. 74 Gradual onset of night blindness, along with photophobia and the loss of central and/or color vision is the next definitive finding, often leading to the diagnosis. Obesity is present in the vast majority (72–86%) of the individuals, although the birth weight may be normal. There is a high prevalence of Type 2 diabetes, hypogonadism, cognitive deficit, labile behavior, speech deficit, renal and cardiac anomalies. 75 The biological defect for the syndrome is an abnormality in immotile cilia that primarily function as the sensory organelle regulating signal transduction pathways. The functional unit of the immotile cilia, or the BBSome, comprises of the cilium, the basal body, the chaperonin complex and other membrane proteins that maintain the function of the cilium. At the time of this writing, mutations in 16 different genes that alter the function of the BBSome at various levels have been identified (BBS1–BBS16). A comprehensive review of BBS can be found at GeneReviews ( https://www.ncbi.nlm.nih.gov/books/NBK1363/ ).

Prader Willi Syndrome (PWS)

PWS is the commonest cause of syndromic obesity around the world (1 in 15,000–25,000 births). 76 It is characterized by severe neonatal hypotonia, eating disorders evolving in several phases (from anorexia and failure to thrive in the early infancy to severe hypephagia with food compulsivity by about 4–8 years of age). 77 Additional features include dysmorphic facies, global cognitive impairment, behavioral abnormalities, hypotonia, delayed motor development and hormonal deficiencies such as growth hormone, hypothyroidism, hypogonadism and ghrelin abnormalities. 76 The genetic defect in PWS is the inactivation of the Prader-Willi critical region (PWCR) located on the 15q11-13 region of the paternal chromosome. The PWCR on the maternal chromosome is imprinted, and therefore epigenetically silenced through methylation, leading to mono-allelic expression of the paternal genes. 78 Majority of cases of PWS are caused by interstitial deletions of the paternal region of the PWCR (65–70%), while others by maternal uniparental disomy (20–30%) and mutations within the imprinting center (2–5%). At least 5 genes, located in the PWCR and expressed in hypothalamus, have been implicated without clarity of their roles: MKRN3 (makorin 3), MAGEL2 (MAGE-like 2), NDN (necdin), NPAP1 (nuclear pore associated protein 1), SNURF-SNRPN (SNRPN upstream reading frame – small nuclear ribosomal protein 1). 79 A recent study of pluripotent stem cells derived neurons from individuals with microdeletion in the PWCR indicates a lower expression of proconvertase 1 (PC1), previously implicated in monogenic obesity, potentially offering a unifying explanation for the phenotype. 80

16p11.2 microdeletion syndrome

This heterozygous deletion of ~593-kb region on chromosome 16 is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder along with severe obesity. Walter et al noted the presence of severe obesity in children with the deletion and performed a large scale analysis using population and disease based cohorts to find an enrichment of the deletion in children and their parents with obesity. 81 Further studies by Bochukova and colleagues indicate that the obesity seen in the children and adults with the 16p11.2 deletion may be mediated via SH2B1 , located in the region. 82

In addition to PWS, and 16p11.2 deletion syndrome, several other obesity-related syndromes with chromosomal defects have been identified. Obesity is often manifested in many, but not all individuals suggesting variable penetrance, or a specific gene that may be differentially involved in different individuals. Examples include deletion of 1p36 (monosomy 1p36 syndrome), 2q37 (brachydactyly mental retardation syndrome; BDMR), 6q16 (PWS-like syndrome), 9q34 (Kleefstra syndrome), 11p13 (WAGR syndrome), and 17p11.2 (Smith Magenis syndrome; SMS). 83 These syndromes may hold the clue to the single genes in the region that could further explain the biology of the disease, e.g. presence of deletion in the BDNF gene in individuals with WAGR syndrome who also presented with obesity. 63

Table 2 provides a list of syndromes known to be associated with obesity, overgrowth syndromes (sometimes confused with obesity) and syndromes where a genetic etiology is not yet elucidated. Many of these syndromes encompass neurodevelopmental abnormalities of varying spectrum. Large-scale studies, such as genome-wide association studies have shown a widespread expression of the loci associated with BMI in the brain. It is plausible that there is heretofore-unidentified shared basis of the obesity and the neurodevelopmental defect(s). However, due to the high prevalence of obesity in the society and the influence of the neuropsychological medications on weight, and the use of food as a behavior modulator, the presence of obesity may be a mere confounder. Nevertheless, neurodevelopmental defects continue to serve as important marker to consider genetic investigation in children with severe, early onset obesity. The interested reader is referred to a recent systematic review by Kaur et al. 72

A] SYNDROMES WITH OBESITY AS A FEATURE
NAME	GENE	Phenotype MIM	Gene/Locus MIM	CLINICAL FEATURES	MODE of INHERITANCE	CHROMOSOMAL POSITION	GENETIC DEFECT

5p13 microduplication syndrome		613174		Developmental delay, autistic behaviour, obesity, lymphedema, hypertension, and macrocephaly	AD	5p13	Microduplication
16p11.2 deletion		611913		Autism, severe early onset obesity, intellectual disability, congenital anomalies	-	16p11.2	del
Albright hereditary osteodystrophy/PHP Type 1 a		103580	139320	Brachymetaphlangism, short stature, obesity, and mental retardation	AD	20q13.32	MS, FS, NS, SS, indel
Alstrom syndrome		203800	606844	Blindness, hearing impairment, childhood obesity, insulin resistance, and T2D	AR	2p13.1	FS, NS, MS
Bardet Biedel syndrome (BBS)				Retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism
BBS 1		209900	209901		AR, DR	11q13.2	MS, NS, SS, FS
BBS 2		615981	606151		AR	16q13	MS, NS, FS, SS, Duplication
BBS 3		209900	608845		AR	3q11.2	NS, del
BBS 4		615982	600374		AR	15q24.1	MS, NS, SS, del
BBS 5		615983	603650		AR	2q31.1	MS, FS, SS, del
BBS 6		605231	604896		AR	20p12.2	MS, FS
BBS 7		615984	607590		AR	4q27	FS, MS, NS, del
BBS 8		615985	608132		AR	14q31.3	MS, SS, indel
BBS 9		615986	607986		AR	7p14.3	FS, SS, del
BBS 10		615987	610148		AR	12q21.2	MS, NS, FS, SS, del
BBS 11		615988	602290		AR	9q33.1	MS, FS
BBS 12		615989	610683		AR	4q27	MS, NS, FS, del
BBS 13		615990	609883		AR	17q22	MS
BBS 14		615991	610142		AR	12q21.32	NS
BBS 15		615992	613580		AR	2p15	NS, SS
BBS 16		615993	613524		AR	1q43-44	NS, SS
BBS 17		615994	606568		AR	3p21.31	MS, NS
BBS 18		615995	613605		AR	10q25.2	NS
BBS 19		615996	615870		AR	22q12.3	SS
BBS 20		617119	608040		AR	2p23.3	SS
BBS 21		617406	614477		AR	8q22.1	MS
Borjeson-Forssman-Lehmann Syndrome		301900	300414	Severe intellectual disability, epilepsy, microcephaly, short stature, obesity, hypogonadism and gynecomastia	XLR	Xq26.2	NS, MS, truncating
Carpenter syndrome		201000	606144	Acrocephaly with variable synostosis, brain malformations, dysmorphic facies, limb abnormalities, heart defects, mental retardation, growth retardation, hypogenitalism and obesity	AR	6p12.1-p11.2	MS, FS, SS, del
CHOPS syndrome*		616368	604417	Congnitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia	AD	5q31.1	MS, SS, del, dup, LOF
Chudley-Lowry syndrome		309580	300032	mental retardation, short stature, mild obesity, hypogonadism and dysmorphism	XLR	Xq21.1	LOF
Cohen syndrome		216550		Developmental delay, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia	AR	8q22.2	MS, NS, del, dup, CNV
Kabuki syndrome/Niikawa-Kuroki syndrome		147920	602113	Facial gestalt, intellectual disability, visceral and skeletal malformations and postnatal short stature with overweight	AD	12q13.12	NS, FS, del
Kleefstra syndrome		610253	607001	Mental retardation, obesity, hypotonia, brachycephaly, characteristic facial features, cardiac anomalies	AD	9q34.3	NS, FS, del
MORM syndrome		610156	613037	Moderate mental retardation, truncal obesity, congenital non-progressive retinal dystrophy, and micropenis	AR	9q34.3	NS
Prader-Willi Syndrome		176270		Failure to thrive & feeding difficulties in infancy, obesity & hyperphagia beginning in childhood, hypotonia, short stature, developmental delay, small hands and feet, genital hypoplasia		15q11.2	del, uniparental disomy
Rubinstein-Taybi syndrome		180849	600140	Short stature, obesity, dysmorphic facies, visual difficulties, eating problems, spine curvature	AD	16p13.3	NS, MS, FS, SS, del
Shashi-X-linked mental retardation				Coarse facies, mental retardation, prominent lower lip, large testis and obesity	XLR		NS, SS, MS
Smith Magenis Syndrome		182290	607642	Intellectual disability, delayed speech and language, sleep disturbances, behavioral problems and obesity	AD	17p11.2	microdel, MS, FS, NS
WAGRO syndrome		612469	612469	Wilms tumor, aniridia, genitourinary anomalies, mental retardation and obesity	?AD	11p13-p12	microdel, chrom inversion
OBHD		613886	600456	Obesity, hyperphagia and developmental delay, memory impairment and learning disability	?AD	9q21.33	MS
Ulnary Mammary syndrome		181450	601621	Posterior limb deficiency, apocrine/mammary gland hypoplasia, delayed puberty, genital anomalies and obesity	AD	12q24.21	MS, NS, del
Unnamed syndrome1		300354	300304	Delayed puberty, hypogonadism, macrocephaly, short stature, central obesity, behavioral problems, pes cavus, abnormal toes	XLR	Xp24	MS, SS, del
Unnamed syndrome2		300860	312180	Dysmorphic facies, large head, synophyrs, low hairline, small genitalia, seizures, mental retardation, overweight and obesity	XLR	Xp24	MS, NS, del

B] OVERGROWTH SYNDROMES
NAME	GENE	Phenotype MIM	Gene/Locus MIM	CLINICAL FEATURES	MODE of INHERITANCE	CHROMOSOMAL POSITION	GENETIC DEFECT

Bannayan-Riley-Ruvalcaba syndrome		153480	601728	Macrocephaly, pseudopapilledema, multiple hemangioma, lipomats	AD	10q23.31	MS, NS, SS, del
Beckwith-Weidemann syndrome		130650	various	Macrosomia, macroglossia, cleft palate, visceromegaly, earlobe creases, neonatal hypoglycemia, embryonal tumors, hemihypertorphy	AD	11p15.5	del, MS
Klippel-Trenaunay-Weber syndrome		14900	-	Large cutanoeus hemangioma with hypertrophy of the related bones and soft tissues	-	8q22.3
Parkes Weber syndrome		608355	139150	multiple arteriovenous malformations under the skin, skeletal hypertorhphy	-	5q13.3	MS, FS, NS, del
Proteus syndrome		176920	164730	asymmetric and disproprotionate overgrowth of one or more body regions, vascular malformations, nevi and abnormal adipose tissue	mosaicism	14q23.31
Silver-Russell syndrome		180860	-	Triangular face with broad forehead and pointed, small chin with a wide mouth, growth retardation (short stature, IUGR), hemihyperplasia	-	7p11.2
Simpson-Golabi-Behmel syndrome		312870	300037	Pre- and post-natal overgrowth, coarse facies, heart defects, other congenital anomalies	XLR	Xq26.2	MS, SS, NS
Sotos syndrome		117550	606681	macrocephaly, overgrowth, developmental delay, advanced bone age, hypotonia, hyperreflexia, motor delay, large hands and feet, may be associated with tumors	AD	5q35	NS, FS, del
Weaver syndrome		277590	601573	macrocephaly, mild hypertonia, advanced bone age, frontal bossing, broad thumb, contractures of elbows, learning difficulty, limb anomalies	AD	7q36.1	NS, MS, del

C] GENETICALLY NON-ELUCIDATED SYNDROMES
NAME	GENE	Phenotype MIM	Gene/Locus MIM	CLINICAL FEATURES	MODE of INHERITANCE	CHROMOSOMAL POSITION	GENETIC DEFECT

Camera-Marugo-Cohen Syndrome	-	604257	-	Obesity, short stature, mental deficiency, hypogonadism, micropenis, contractures of the fingers, cleft lip-palate	-	-	-
Clark-Baraitser Syndrome	-	300602		Macrocephaly, mental retardation, ‘square’ forehead, prominent features, tall stature, large ears, obesity and macroorchidism	-	-	-
MEHMO syndrome	-	300148	-	Mental retardation, epileptic seizures, hypogonadism, microcephaly and obesity	?Mitochondrial	Xp22.13-p21.1	-
MOMES syndrome	-	606772	-	Mental retardation, obesity, blepharophimosis, astigmatism, maxillary hypoplasia, mandibular prognathism	?AR	-	-
MOMO syndrome	-	157980		Macrosomia, Obesity, Macrocephaly, Ocular abnormalities	-	-	-
Morgagni-Stewart-Morel Syndrome	-	144800	-	Hyperostosis frontalis interna, Galactorrhea, Hyperprolactinemia, diabetes mellitus, hyperphosphatasia, obesity, hypertrichosis	?AD	-	-
1p36 deletion syndrome	-	607872	-	Hypotonia, developmental delay, growth abnormalities, obesity and craniofacial dysmorphism	-	1p36	del
2p25.3 deletion syndrome		616521	-	Intellectual disability, Obesity, Behavioral problems, Sleep disturbances	AD	2p25.3	del

AD = Autosomal dominant, AR= Autosomal recessive, XLR= X-linked recessive, MS = missense mutation, NS = nonsense, SS = splice site, LOF= loss of function, del = deletion, dup = duplication.

For complete description and references, refer to Online Mendelian Inheritance in Man: omim.org using the MIM numbers. Additional info at Gene Reviews: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews ® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1116/

DIAGNOSTIC APPROACH

With the high prevalence of obesity in the modern society, it is imperative that the astute clinician is educated about the indications for genetic testing. For children with severe early onset obesity (BMI > 120% of 95 th percentile of CDC 2000 for age), it is useful to enquire for history suggestive of hyperphagia, endocrinological co-morbidities, and a detailed pedigree including history of consanguinity. Assortative mating can confound family history, and identification of patterns indicative of autosomal dominant, or de novo inheritance is helpful. Individuals with neurodevelopmental and cognitive difficulties may lead to a consideration of tests such as high-resolution karyotype, methylation studies of chromosome 15, or comparative genomic hybridization (CGH) array for chromosomal defects. Based on presence of other features suggestive of syndromic obesity (see Table 2 ), or other characteristic findings such as prolonged diarrhea ( PCSK1 ), or hypoglycemia and orange hair ( POMC ) single gene or panels such as the BBS panel may be considered. Candidate gene panels for genetic obesity ( LEP, LEPR, POMC, PCSK1 ) are available in some laboratories and may be considered on a case-by-case basis (see: Genetic Testing Registry. Available at https://www.ncbi.nlm.nih.gov/gtr/ ).

Assessment of leptin level is useful if there is a consideration of LEP deficiency. As leptin levels are generally elevated with adiposity, it is more difficult to ascertain LEPR deficiency by measurement of leptin levels. If an autosomal dominant mode of inheritance is established for children with severe early onset obesity, MC4R sequencing (1 exon) is widely available. A number of research efforts for rare genetic variants for children with severe early onset obesity are ongoing ( www.clinicaltrials.gov ). It is important to provide basic counseling prior to genetic testing. Should this be a barrier, a referral to a skilled specialist is suggested.

THERAPEUTIC CONSIDERATION

The characterization of the etiology of a monogenic or syndromic cause of obesity often ends a diagnostic odyssey for the etiology of the clinical condition. Additionally, the promise of targeted treatment in the rapidly progressive field of personalized medicine provides hope for the families struggling with management of obesity and associated comorbidities in children.

For most of the genetic causes of obesity, management of nutrition and physical activity remains the first line of therapy. Children with genetic causes of obesity, such as MC4R and LEPR mutations have been maintained at lower levels of adiposity with long-term restriction of caloric intake (Lennerz B, Personal Communication). In children with PWS, the nutritional guidelines change with the phases of eating patterns over time. In the hyperphagia phase, weight maintenance has been documented with intakes of 7 kcal/cm of height/day, and sample calorie guidelines have been published by Prader Willi Syndrome Association. 84 There are no systematic prospective studies on the use of these guidelines, and treatment needs to be individualized for each child. Although studies have proposed use of ketogenic and other limited diets 85 , the current guidelines continue to recommend a balanced calorie reduction with maintenance of the usual macronutrient proportions (60% carbohydrate, 15% protein and 25% fat), with emphasis on low glycemic index and slow-release carbohydrates. 84

Medications such as injectable recombinant leptin for treatment of leptin deficiency 29 , or biologically inactive leptin 27 present a rare, but valuable opportunity for treatment. A promising new therapy for POMC deficiency is Setmelanotide, an eight-amino-acid cyclic peptide (RM-493) melanocortin-4 –receptor agonist without the side-effects of hypertension and increased erectile dysfunction 42 . Kuhnen et al report the short-term use of setmelanotide in 2 adult females with POMC deficiency, 21- and 24-years old with baseline BMI of 49.8 kg/m2 (SDS 4.52) and 54.1 kg/m2 (SDS 4.78). Both the patients received treatment for 12 weeks with decrease in weight from 20–26 kg (decrease of 13.4–16.6%), and a marked improvement in satiety and quality of life (clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02896192","term_id":"NCT02896192"}} NCT02896192 , http://geneticobesity.com/ ). 42 This therapy also appears to offer promise in animal models for PWS. 86 Another drug, Beloranib, a Methionine Peptidase 2 (MetAP2 ) inhibitor, that influences fat metabolism, synthesis and storage, was found to reduce hunger and restored balance to the production/utilization of fat is in early clinical trials. 87 Nasal oxytocin has been tried for therapy in PWS based on the finding of decreased oxytocin neurons in an attempt to improve behavioral and adiposity phenotype. 88 – 90 A number of other MC4R receptor agonists are in preclinical and early clinical trials. 50 Pharmacological chaperones that increase the expression of the cell surface expression of MC4R is a promising approach. 91 , 92 An important consideration for neuropeptides used in the treatment of genetic forms of obesity is an acceptable route of administration that will provide sufficient central nervous system penetrance for its action on the centers for weight regulation.

Bariatric surgery is increasingly being used as the effective treatment of severe obesity with or without concomitant co-morbidities in adolescents 93 and adults 94 . Soper et al reported the use of bariatric surgery as a treatment of morbid obesity in 7 adolescents with PWS and 18 genetically normal young adults. The individuals with PWS reached a plateau of weight loss faster, and 3 individuals required revision surgeries to improve weight loss. 95 Forty years later, the debate on the use of bariatric surgery for the treatment of genetic and syndromic forms of obesity continues. In a retrospective review of 60 subjects with PWS undergoing bariatric surgery, Scheiman et al reported a myriad of serious complications such as wound infection, deep vein thrombosis, pulmonary embolism, splenectomy with the surgery, weight rebound and poor response to surgery with some requiring revision and death in 2 subjects. 96 The surgical techniques used in this report from 2008 have evolved over time. Two recent reports, one from Saudi Arabia (n = 24) 97 and another from China (n = 3) 98 have reported successful use of laparoscopic sleeve gastrectomy in individuals with PWS. Alqahtani et al performed a case-control (1:3) study of 24 subjects with PWS (mean age 10.9 years, mean BMI 46.2 kg/m2; 66.7% with ≥ 3 comorbidities). They reported a 22.2 (±14.6) % reduction in BMI in cases with PWS compared with 37.9 (±12.1)% in controls (p = 0.05). There was no statistical difference in % excess weight loss in the cases as compared to non-genetic obese controls till 3 years of follow-up with some rebound noted in the cases at 5-years of follow-up. The families reported an improvement in hyperphagia and food-seeking behavior that has largely been attributed to a reduction in the levels of ghrelin after the surgery as noted in the report from China. 98 The same group has previously published favorable reports in subjects with PWS, BBS and ALMS1 syndrome 99 with mixed response from surgeons in the US 100 and France. 101 Regardless of the debate, the need for multi-disciplinary pre- and post-operative care of individuals with syndromic obesity or intellectual disability with careful follow-up is advocated 102 , and the need for large scale systematic studies for long-term outcomes remains.

EPIGENETIC MODIFICATIONS IN OBESITY

While genetic perturbations play an important role in determining individual susceptibility to obesity, the role of environment, and gene-environment interactions remains; leading to a growing interest in the role of epigenetics in the development of obesity and obesity-related comorbidities. This offers a logical explanation for the growing epidemic of obesity over the past few decades without a radical change in the genome. In multicellular organisms like humans, the genetic code is homogenous throughout the body, but the expression of the code can vary in the different cell types. Epigenetics is the study of heritable regulatory changes in the genetic expression without alterations in the nucleotide sequence. 103 Epigenetic modifications can be considered as the differential packaging of the DNA that either allows or silences the expression of the certain genes across tissues. Environmental and dietary factors or gut microbiota, can influence the epigenetic programming of parental gametes, fetus and early postnatal development, or through the various periods of life to influence epigenetic programming. 104

Epigenetic mechanisms

The currently known epigenetic mechanisms include DNA methylation, histone modifications, and microRNA-mediated regulation, which can be passed on mitotically (through cell division) or meiotically (transgenerational inheritance).

DNA methylation

In DNA methylation, a methyl group can be added to a cytosine with a guanine as the next nucleotide (CpG site) by DNA methyltransferases (DNMTs). These CpG sites are frequently found in the promoter regions of the genes, and a methyl group addition acts as a steric obstacle for the joining of the transcription factors and the expression of the gene: usually hypermethylation is associated with transcriptional repression, and hypomethylation with activation. 103 Candidate gene methylation changes have been implicated in obesity, appetite control and metabolism, insulin signaling, immunity, inflammation, growth, and circadian clock regulation. 104 In a genome wide study of the CpG methylation sites of 479 adults of European origin, an increased methylation at the HIF3A (hypoxia-inducible factor 3a) locus was reported in the blood and adipose tissue. 105 Similar associations were also seen in early life where higher methylation at the same sites were associated with greater infant weight and adiposity. 106 As hypoxia response has been reported during obesity, this finding provides direct evidence that perturbation of the HIF signaling plays an important role in the obesity, metabolism and downstream adverse responses to obesity. 105 Similarly, both the LEP and POMC genes, prominent in the weight regulation pathway have CpG islands, where methylation can affect their expression. In a study of methylation at the LEP gene in the maternal, placental and cord blood samples, Lesseur et al found increased maternal blood methylation with pre-pregnancy obesity, cord blood methylation with SGA infants and pre-pregnancy smoking and a good correlation of maternal blood LEP DNA methylation with infant blood methylation. 107 Similarly, increased LEP methylation was observed in men born after prenatal exposure to wartime (Dutch) famine in 1944–45 compared to their unexposed same-sex siblings. 108 Some other genes investigated in the context of obesity and metabolism include ADIPOQ (adiponectin), PGC1α (peroxisome proliferator-activated receptor coactivator 1 α), IGF-2 (insulin-like growth factor 2), IRS-1 (insulin receptor substrate 1), and LY86 (lymphocyte antigen 86). 104 Epigenetic markers have also been used as predictor(s) for long-term weight loss (or regain). In a study of 18 men who underwent ≥ 5% weight loss after an 8-week nutritional intervention, Crujeiras et al report higher pre-intervention methylation levels of POMC , and lower NPY methylation in the individuals who maintained weight loss. 109 POMC methylation is also being investigated as an early predictor of metabolic syndrome. 110 DNA methylation studies remain an active area of investigation in both animals and humans that will continue to guide our understanding on the effects of genes, environment and their interaction.

Histone modification

Histones are proteins responsible for DNA packaging, made up of a globular domain and an N-terminal tail domain. The highly basic N-terminal tails protrude from the nucleosome and are exposed to covalent reactions such as methylation, acetylation, ubiquitination and phosphorylation. Depending on the combination of these covalent reactions, the DNA will be accessible for translation, repair, replication and recombination. 111 Histone modifications are involved in the epigenetic regulation of adipogenesis and can play an important role in obesity development. Modulation of five key regulatory genes of adipogenesis, pre-adipocyte factor-1 (Pref-1), CCAAT-enhancer-binding protein β (C/EBP β), C/EBPα, PPARγ, and adipocyte protein 2 (aP2), is regulated by histone modifications during adipocyte differentiation. 112 The histone deacetylase (HDAC) family of proteins plays an important role in the regulation of gene transcription in response to stress and energy metabolism. A study of the chromatin expression profile of the liver cells in animals fed high fat diet compared to those fed control diet showed chromatin remodeling by HDAC resulting in changes in expression profile of hepatic transcription factors HNFα, CCAAT/enhancer binding protein α (CEBP/α), and FOXA1. 113 They also demonstrated that these changes are irreversible, when the animals revert to the normal diet in one species, while being transient in another emphasizing the variable expressivity of modifications in a framework of different genetic background. 114 A differential expression of the HDAC proteins in also seen in the hypothalamus in the fasting/fed states and high-fat diet-induced obesity. 115

Micro-RNAs (miRNA) are short noncoding RNA sequences 18 to 25 nucleotides long capable of regulating gene expressions by gene silencing and post-transcriptional changes. 116 miRNA play an important role in various biological processes, including proliferation and differentiation of adipocytes, and have been shown to be associated with insulin resistance and low-grade inflammation seen in obese individuals. 117 A significant association with increased levels of certain miRNA (miR-486-5p, miR-486-3p, miR-142-3p, miR-130 b, and miR-423-5p) was seen with BMI in children with obesity, with a significant change in the profile of 10 miRNAs with weight change. 118 Zhao et al identified miRNA as a signature for weight gain and showed that the individuals with a high-risk score for 8 of these miRNAs had over 3-fold higher odds of weight gain. 119 Changes in adipocyte-derived exosomal miRNAs is also seen following weight loss and decrease in insulin resistance after gastric bypass. 120 All the emerging evidence lends support to the important role of miRNA in obesity and the associated metabolic changes that can serve as biomarkers, or potentially therapeutic targets for intervention.

Epigenetic changes caused by the intrauterine and early development environment

The intrauterine environment plays a crucial role in the development of the fetus and has been shown to play a role in the long-term epigenetic programming that may be transmitted to the progeny. Epidemiological studies of two large cohorts exposed in utero to serious nutritional deficits during the Second World War, who later lived in contrasting conditions, returning to normal nutrition in the case of the Dutch cohort exposed to the “Dutch Famine” 121 , and conversely, persisting conditions of poor nutrition in case of children who survived the dramatic siege of Leningrad 122 , 123 , have provided clues to the role of epigenetics. The Dutch cohort exposed to enriched nutritional conditions showed less DNA methylation of the imprinted IGF2 gene compared to their same sex siblings. They also had a higher incidence of chronic metabolic disease compared to the Russian cohort that continued to live in deprived condition supporting the theory of fetal programming . Animal studies have provided further evidence to support this theory. Mice born to undernourished mothers and postnatally exposed to high fat diet have shown adverse cardiometabolic profile. 124 Besides undernutrition, presence of maternal obesity or metabolic dysfunction also predisposes infants to obesity. There is also evidence that this programming may be transgenerational that continues even after the environmental influence is eliminated, thus propagating the cycle of obesity and metabolic syndrome. 125

Endocrine disrupting chemicals (“Obesogens”)

In the context of epigenetic changes, it is important to review the role of endocrine disrupting chemicals (EDCs termed “obesogens”) on the effects on adipose tissue biology, the hormonal milieu and the influence on the homeostatic mechanisms of weight regulation. Epidemiological studies have provided evidence for the presence of obesity and metabolic changes in offspring of mothers exposed to EDCs likely mediated by epigenetic changes. Offspring of pregnant animals exposed to polycyclic aromatic hydrocarbons during gestation have increased weight, fata mass, as well as higher gene expression of PPARγ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ that extended through the grand-offspring mice. 126 Genomewide epigenetic study in the adult mice born following perinatal exposure to bisphenol A at human physiologically relevant disease, showed an enrichment of significant differentially methylated regions in metabolic pathways among females. DNA methylation as a mediator for the metabolic phenotype was identified in Janus kinase-2 ( Jak-2 ), retinoid X receptor ( Rxr ), regulatory factor x-associated protein ( Rfxap ), and transmembrane protein 238 ( Tmem 238 ). 127 A comprehensive review of the effects of EDCs is outside the scope of this review, but suffice to say that there is convincing evidence from human and animal studies of epigenetic mechanisms in the effects of EDCs on childhood obesity and metabolic dysfunction.

Genetic factors and the environmental factors that influence the expression of these genes play a large role in the development of obesity in children, adolescents and young adults. Thoughtful consideration of genetic causes and an understanding of the growing evidence of the epigenetic changes that influence the burgeoning epidemic of obesity provide valuable tools for the clinician in the management of obesity.

Acknowledgments

Funding Source: This work was supported in part by the NIH NIDDK grant K23DK110539-02, ADA 1-16-PDF-113, and NIH P30 DK040561 to VVT.

Financial Disclosure: The author has no financial relationships relevant to this article to disclose.

Conflict of Interest: The author has no potential conflicts of interest to disclose.

Lilly Opens $700M R&D Center in Boston for Genetic Medicines

The new Lilly Seaport Innovation Center in Boston

Lilly’s newly opened Seaport Center in Boston

Courtesy of Eli Lilly and Company

Eli Lilly’s new research and development facility in Boston’s Seaport district will focus on DNA- and RNA-based therapies, as well as other priority areas such as diabetes and obesity.

Eli Lilly on Tuesday debuted in America’s biggest biotech hub—Boston—with a new facility dedicated to the research and development of cutting-edge genetic therapies.

Dubbed the Lilly Seaport Innovation Center (LSC), the new site will expand the pharma’s U.S. footprint by 346,000 square feet and will be able to house 500 scientists and researchers. The LSC can also accommodate 200 staff from within the innovation hub Lilly Gateway Labs, which the pharma uses to connect earlier stage biotechs with its platforms and expertise.

The LSC will work on advancing RNA- and DNA-based therapies while also allotting some its resources to discovering new drug targets for Lilly’s priority disease areas, such as diabetes, obesity and cardiovascular diseases. The pharma will also leverage the LSC for R&D in neurodegeneration and chronic pain.

Daniel Skovronsky, chief scientific officer and president of Lilly Research Laboratories, in a statement said that the opening of the LSC will allow the pharma to collaborate “with leading institutions and new talent to continue delivering transformative medicines for the people who need them the most.”

With the LSC’s opening, Lilly brings the obesity competition closer to its chief rival Novo Nordisk, which in February 2024 opened an R&D site in the Boston area, according to the Boston Business Journal . The pharma first announced this expansion in March 2023, revealing at the time that the site will similarly focus on genetic therapies.

Lilly has steadily been gaining ground on Novo in the weight-loss drug race. In the second quarter of 2024, Lilly’s product sales impressed investors by easily beating consensus forecasts. Meanwhile, investors found Novo’s performance disappointing in Q2, with its shares dropping more than 7% shortly after the pharma released its earnings report.

Supply headwinds can partly account for this disparity, with Lilly clearing up the U.S. shortages for all doses of type 2 diabetes medication Mounjaro and weight-loss drug Zepbound. By contrast, while Novo has made progress on stabilizing its supply, one dose of Wegovy still has limited availability .

On the efficacy front, Lilly appears to have Novo beat as well. Last month, a study published in JAMA Internal Medicine found that Mounjaro could elicit 2.4% greater weight-loss than Novo’s Ozempic—and this gap widened even further through six and 12 months of treatment.

The rivals are continuing to compare their incretin therapies against each other. Lilly is currently conducting the Phase IIIb SURMOUNT-5 head-to-head study in overweight or obese adults without type 2 diabetes. Results from this trial are expected in November 2024. Meanwhile, Novo is looking to challenge Zepbound with its next-generation therapy CagriSema with a Phase III study that is expected to wrap up in the second half of 2025.

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Lilly Opens $700M R&D Center in Boston for Genetic Medicines
Eli Lilly on Tuesday debuted in America's biggest biotech hub—Boston—with a new facility dedicated to the research and development of cutting-edge genetic therapies.. Dubbed the Lilly Seaport Innovation Center (LSC), the new site will expand the pharma's U.S. footprint by 346,000 square feet and will be able to house 500 scientists and researchers.

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