This report constitutes the sixth update of the human obesity gene map incorporating published results up to the end of October 1999. Evidence from the rodent and human obesity cases caused by single gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTL) uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, pig and chicken models, association and linkage studies with candidate genes and other markers is reviewed. Twenty-five human cases of obesity can now be explained by variation in five genes. Twenty Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models reaches now 98. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 89 reports of positive associations pertaining to 40 candidate genes. Finally, 44 loci have linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes can be found on all autosomes, with chromosomes 14 and 21 showing each one locus only. The number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes continues to increase and is now well above 200.

The aim of this study was to determine the respective contribution of abdominal visceral adipose tissue (AT) accumulation and insulin resistance (IR) to the determination of a comprehensive cardiovascular metabolic risk profile in 108 postmenopausal women not receiving hormone therapy. Insulin sensitivity (M/I) was determined by a hyperinsulinemic-euglycemic clamp, and visceral AT area was measured by computed tomography. Median values of visceral AT (133.9 cm 2 ) and insulin sensitivity (0.010189 mg ⅐ kg ؊1 ⅐ min ؊1 ⅐ pmol ؊1 ) were used to form four subgroups: 1) low visceral AT-low IR (n ‫؍‬ 35), 2) low visceral AT-high IR (n ‫؍‬ 19), 3) high visceral AT-low IR (n ‫؍‬ 19), and 4) high visceral AT-high IR (n ‫؍‬ 35). Women with isolated IR (low visceral AT and high IR) were characterized by significantly higher fasting and 2-h glycemia and higher fibrinogen, triglyceride, and VLDL-apolipoprotein (apo)B concentrations than women with low visceral AT and low IR (P < 0.05). The plasma lipid-lipoprotein profile and inflammatory markers were not significantly different between women with high visceral AT and low IR and women with low visceral AT and low IR. Women with high visceral AT and high IR had higher fasting and 2-h glycemia, triglyceride, and VLDL-apoB levels; lower apoAI and HDL 2 cholesterol levels; as well as higher C-reactive protein and interleukin-6 concentrations than women with low visceral AT and low IR (P < 0.05). In addition, 15 of the 35 women (42.9%) in the high visceral AT and high IR group were newly diagnosed with type 2 diabetes, whereas no women were diagnosed with type 2 diabetes in the group of women with low visceral AT and low IR. These results show that although the presence of high IR in its isolated form is associated with some metabolic alterations, it is the combination of both high visceral AT and high IR that is the most detrimental for the metabolic health in postmenopausal women. Diabetes 54:770 -777, 2005 P ostmenopausal women are at higher risk of cardiovascular disease (CVD) than premenopausal women. This increased CVD risk after menopause has been partly attributed to the increment in visceral adipose tissue (AT) deposition and worsening insulin-stimulated glucose disposal observed during the menopause transition (1,2). There is also evidence indicating that there is an increase in insulin resistance (IR) with aging (3). Insulin resistance has been suggested as an important risk factor in the development of the metabolic syndrome, a cluster of abnormalities comprising glucose intolerance, dyslipidemia, high blood pressure, and impaired fibrinolysis activity that is associated with increased risk of developing type 2 diabetes and CVD (4). It is well demonstrated that obesity is a risk factor for type 2 diabetes and CVD (5). In addition, body fat distribution is also related to the risk of type 2 diabetes and CVD, and studies have shown that individuals with increased accumulation of visceral AT appear to develop the metabolic syndrome more frequently than those with an incr...

Obesity and insulin resistance are common features of Type 2 Diabetes. A new protein called resistin has been shown to be secreted by adipocytes in mice and to influence insulin sensitivity. The goal of the present study was to investigate the associations between one polymorphism (g-420C>G) of the human resistin gene and phenotypes related to adiposity and glucose metabolism. We genotyped 725 (including 42 diabetics) adult subjects participating in the Quebec Family Study (QFS) by a minisequencing method. Forty-two were diabetic subjects. Phenotypes measured were: body mass index (BMI) and waist circumference (WC), % body fat (PFAT) and fat mass (FM) assessed by under water weighing, abdominal total, subcutaneous and visceral fat assessed by computed tomography and fasting plasma glucose, insulin and C-peptide and their responses to an oral glucose tolerance test (OGTT). Comparisons between genotypes were performed in non-diabetic men (no.=280) and women (no.=403) separately by analyses of covariance (ANCOVA). Among men, g-420 G homozygotes had less visceral fat (p < 0.05), lower levels of acute insulin responses to an OGTT and lower levels of C-peptide in a fasting state and in responses to an OGTT than carriers of the C allele (p < 0.01). These associations were independent of age and adiposity but were not observed in women. These results suggest that in men, the human resistin gene is associated with reduced amount of visceral obesity and lower insulin secretory responses to a glucose load.

Together, these results showed that PPARG Pro12Ala and PPARGC1A Gly482Ser variants are associated, alone and in interaction, with insulin and glucose homeostasis and suggest that gene-gene interactions should be taken into account in candidate gene studies of T2DM to identify subjects with markedly different risks of developing the disease.