The Human Obesity Gene Map: The 1997 Update

Chagnon, Yvon C.; Pérusse, Louis; Bouchard, Claude

doi:10.1002/j.1550-8528.1998.tb00318.x

Cited by 85 publications

(44 citation statements)

References 114 publications

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“…Where the genetic defects underlying several monogenic forms of obesity in mice have been elucidated within recent years, little progress has been achieved regarding the genetic basis of the common forms of obesity in humans. 23 The recent study showing that mutations in the POMC gene may cause early onset severe obesity, 7 together with the studies implicating the POMC gene in the agouti mouse model, as well as linkage studies, 8,12,13 make this gene a relevant candidate for the inherited basis of human obesity.…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity

et al. 1999

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OBJECTIVE: Mutations in the human gene encoding the polyhormone peptide proopiomelanocortin (POMC) are associated with obesity in rare cases and the gene co-localizes with a reported quantitative trait loci (QTL) for variations in circulating leptin levels and fat mass on human chromosome 2p21. In this study we have used polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) analysis, to test whether variations in the human POMC gene are associated with human obesity. DESIGN AND SUBJECTS: Primary mutational analysis was performed on the coding region of the POMC gene and 500 bp of the putative promoter region, by single strand conformational analysis and sequencing, in 56 subjects with juvenile onset obesity (body mass index (BMI) ! 31 kgam 2 at the draft board examination). The prevalence of two polymorphisms were further studied in 156 obese and 205 control subjects, and in a population based cohort of 380 extensively characterized young healthy subjects. RESULTS: We have identi®ed a total of six gene variants, ®ve were silent nucleotide substitutions (No51(promoter) g?c, No670(5 H UTR)g?a, No4512(codon6)c?t CysaCys, No7726(codon116)c?t LeuaLeu) of which one was prevalent (No8246(3 H UTR)c?t) and one variant changed an amino acid (No8086(codon236)g?c ArgaGln). The amino acid substitution was only seen in one subject. Comparing the prevalence of the frequent No8246 silent polymorphism, in an association study comprising 156 subjects with juvenile onset obesity and 205 randomly sampled control subjects (mean BMI 23.5 AE 4.7 kgam 2 ), did not show any relationship to obesity. Also, comparing the prevalence of a known 9 bp insertionadeletion variant in the coding region of the gene between obese and lean, showed no association to obesity. Furthermore, analyzing a population based cohort of 380 young healthy Caucasians for the prevalent 3 H UTR polymorphism as well as the 9 bp insertionadeletion variant did not show any association to deviations in body fat contents or fasting serum leptin concentrations. CONCLUSION: In conclusion, it is unlikely that variations in the coding region and the putative promoter of the POMC gene are a major cause of juvenile onset human obesity.Keywords: juvenile onset obesity; proopiomelanocortin gene; obesity genetics; body fat; leptin IntroductionHuman obesity is a complex disorder determined by both inheritance and environment. Family studies 1 and studies of twins, 2,3 as well as adoptees reared apart 4,5,6 show that from 30 ± 70% of the variation in adiposity is determined by genetic factors. However, little is known about the mode of inheritance and no gene variants responsible for the common form of human obesity has so far been identi®ed.A recent study by Krude et al 7 has demonstrated that early onset severe obesity, adrenal insuf®ciency and red hair pigmentation, in two patients, is caused by mutations in the human proopiomelanocortin (POMC) gene. Moreover, a study by Comuzzie et al 8 has shown evidence of linkage between variations in circulating...

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Section: Discussionmentioning

confidence: 99%

Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity

et al. 1999

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“…In that report, suggestive linkages between several microsatellite markers from 1p32 to p22 and for BMI, fat mass, and fasting insulin were found. In fact, chromosome 1 is one of the few chromosomes showing at least 3 putative loci related to obesity in both arms (40).…”

Section: Fernández-real and Associatesmentioning

confidence: 99%

Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients.

Fernández‐Real¹,

Vendrell²,

Ricart³

et al. 2000

Diabetes Care

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Abbreviations: EASIA, enzyme-amplified sensitivity immunoassay; FSIVGTT, frequently sampled intravenous glucose tolerance test; PCR, polymerase chain reaction; sTNFR2, soluble fraction of tumor necrosis factor-␣ receptor; TNF-␣, tumor necrosis factor-␣; TNFR1, tumor necrosis factor-␣ receptor 1; TNFR2, tumor necrosis factor-␣ receptor 2; UTR, untranslated region; WHR, waist-to-hip ratio.A OBJECTIVE -Mice lacking the tumor necrosis factor-␣ receptor 2 (TNFR2) gene fed a highfat diet gain less weight and display reduced leptin and insulin levels. In humans, plasma levels of the soluble fraction of TNFR2 (sTNFR2) circulate in proportion to the degree of insulin resistance. The purpose of this study was to evaluate a polymorphism in the 3Ј untranslated region of the TNFR2 gene on chromosome 1 in relation to BMI, leptin levels, and insulin resistance.RESEARCH DESIGN AND METHODS -Using single-strand conformation polymorphism, the polymorphism was analyzed in 107 nondiabetic subjects (60 women, 47 men) and in 110 consecutive patients with type 2 diabetes (79 women, 31 men). In a subset of 33 healthy subjects, insulin sensitivity (minimal model analysis) was also evaluated.RESULTS -Four alleles of the TNFR2 gene were identified (A1, A2, A3, and A4). BMI and serum leptin levels were significantly increased in young carriers of the A2 allele. Plasma sTNFR2 levels were similar among the different TNFR2 gene variants. However, in subjects who did not carry the A2 allele, in young subjects, and in women, plasma sTNFR2 levels were proportional to BMI and leptin levels. In the study sample, carriers of the A2 allele (n = 18) showed significantly increased BMI, fat mass, waist-to-hip ratio, serum total and VLDL triglyceride levels, and leptin levels and had a lower insulin sensitivity index than noncarriers of the A2 variant (n = 15). The frequency of the different alleles among diabetic subjects was similar to that in the control population. However, diet-treated diabetic subjects (n = 49) who were carriers of the A2 allele exhibited significantly higher BMI and leptin levels than diet-treated noncarriers of the A2 allele.CONCLUSIONS -The presence of the A2 allele in the TNFR2 gene may predispose subjects to obesity and higher leptin levels, which may in turn predispose them to insulin resistance or vice versa. The TNFR2 gene may be involved in weight-control mechanisms.

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“…Thus, deposits of the male or central pattern are associated with greater insulin resistance than deposits in the female or peripheral sites, particularly the lower body or buttock [77,78] 82]. The number of obesity loci identified is large and growing [83], and therefore it is likely to be multifactorial. Intra-abdominal fat seems to be particularly important [84].…”

Section: Insulin Adiposity and Diabetesmentioning

confidence: 99%

Obesity, diabetes and the central nervous system

et al. 1998

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Nearly 25 years ago, one of us wrote a collaborative review entitled ªObesity and Diabetes, the Odd Coupleº [1]. At that time we pointed out that obesity was a risk factor for diabetes mellitus, despite the fact that most obese people do not have and never will develop diabetes. We also pointed out that obesity is associated with insulin resistance and hyperinsulinaemia, whereas in the non-obese, diabetes is characterized by hypoinsulinaemia and hyperglycaemia. We asked, how is it that such different syndromes interact so closely? We concluded that while these two syndromes are likely to have independent risk factors and mechanisms, their known interactions made it likely that shared metabolic defects are involved in their pathogenesis. We concluded that further studies into the pathophysiology of these syndromes were needed to explain this apparently paradoxical association.In the intervening years, considerable advance has been made into the pathophysiology of both syndromes. First, it is now clear that hyperglycaemia in Type II (non-insulin-dependent) diabetes is not the result of a regulatory failure, but is an adaptive response to impaired beta-cell function and insulin resistance, and we have reviewed this extensively [2]. More recently, obesity has similarly been shown to result from a dysregulation of food intake and energy expenditure rather than a loss of control over food intake [3±5]. In either case the critical variable (blood glucose or body adiposity) is defended at an abnormal level due to a regulatory defect, and both hyperglycaemia and obesity have undesirable long-term metabolic and vascular complications. What is now apparent is that there is overlap among the hormones, neuropeptides, and receptors involved in these two disorders, and it is our belief that it is this sharing which plays a prominent role in their association.In this article, we review our present understanding of the major elements of the feedback loops for body weight regulation in order to provide a comprehensive framework within which to place a torrent of new studies. We focus primarily on recent data implicating insulin, leptin, and hypothalamic neuropeptides as major elements. In this process we point out where the energy balance and glucose regulating systems intersect and indicate where common signalling mechanisms participate in their association. We conclude by synthesizing this information into a model that can explain how a single underlying set of pathophysiological factors can lead first to obesity and subsequently to Type II diabetes. Diabetologia (1998) 41: 863±881

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The Human Obesity Gene Map: The 1997 Update

Cited by 85 publications

References 114 publications

Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity

Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity

Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients.

Obesity, diabetes and the central nervous system

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