Search

The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects., Maintenance of body weight and energy homeostasis requires balance between energy intake and expenditure and is achieved via the interaction between central and peripheral signals. The central melanocortin system is [...]

OBJECTIVE--The study objective was to determine the key early mechanisms underlying the beneficial redistribution, function, and inflammatory profile of adipose tissue in 11β-hydroxysteroid dehydrogenase type 1 knockout (11β-[HSD1.sup.-/-]) mice fed a high-fat (HF) diet. RESEARCH DESIGN AND METHODS--By focusing on the earliest divergence in visceral adiposity, subcutaneous and visceral fat depots from 11β-[HSD1.sup.-/-] and C57B1/6J control mice fed an HF diet for 4 weeks were used for comparative microarray analysis of gene expression, and differences were validated with real-time PCR. Key changes in metabolic signaling pathways were confirmed using Western blotting/immunoprecipitation, and fat cell size was compared with the respective chow-fed control groups. Altered adipose inflammatory cell content and function after 4 weeks (early) and 18 weeks (chronic) of HF feeding was investigated using fluorescence (and magnetic)-activated cell sorting analysis, immunohistochemistry, and in situ hybridization. RESULTS--In subcutaneous fat, HF-fed 11β-[HSD1.sup.-/-] mice showed evidence of enhanced insulin and β-adrenergic signaling associated with accretion of smaller metabolically active adipocytes. In contrast, reduced 11β-[HSD1.sup.-/-] visceral fat accumulation was characterized by maintained AMP kinase activation, not insulin sensitization, and higher adipocyte interleukin-6 release. Intracellular glucocorticoid deficiency was unexpectedly associated with suppressed inflammatory signaling and lower adipocyte monocyte chemoattractant protein-1 secretion with strikingly reduced cytotoxic T-cell and macrophage infiltration, predominantly in visceral fat. CONCLUSIONS--Our data define for the first time the novel and distinct depot-specific mechanisms driving healthier fat patterning and function as a result of reduced intra-adipose glucocorticoid levels. Diabetes 60:1158-1167, 2011, Accumulation of visceral fat strongly increases the risk of cardiometabolic disease, whereas peripheral fat accretion is relatively protective (1-3). Pronounced visceral adiposity, loss of subcutaneous adipose tissue, and metabolic disease [...]

OBJECTIVE--Large-scale genome-wide association (GWA) studies have thus far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children and adolescents. RESEARCH DESIGN AND METHODS--Seventeen variants representing 16 obesity susceptibility loci were genotyped in 1,252 children (mean ± SD age 9.7 ± 0.4 years) and 790 adolescents (15.5 ± 0.5 years) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analyzed with previously reported data ([N.sub.total] = 13,071 children and adolescents). RESULTS--In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta-analysis showed directionally consistent associations with BMI for all 13 variants, of which 9 were significant (0.033-0.098 SD/allele; P < 0.05). The near-TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 x [10.sup.-11]). Effect sizes for BMI tended to be more pronounced in children and adolescents than reported earlier in adults for variants in or near SEC16B, TMEM18, and KCTD15, (0.028-0.035 SD/allele higher) and less pronounced for rs925946 in BDNF (0.028 SD/allele lower). Each additional effect allele in the GPS-17 was associated with an increase of 0.034 SD in BMI (P = 3.6 x [10.sup.-5]), 0.039 SD, in sum of skinfolds (P = 1.7 x [10.sup.-7]), and 0.022 SD in waist circumference (P = 1.7 x [10.sup.-4]), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference). CONCLUSIONS--Most obesity susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. Whereas the association of some variants may differ with age, the cumulative effect size is similar. Diabetes 59:2980-2988, 2010, Over the past three decades, the prevalence of obesity has reached epidemic proportions not only in adults, but in children and adolescents alike (1,2). A high BMI during childhood and [...]

OBJECTIVE--A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. RESEARCH DESIGN AND METHODS--Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157-159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. RESULTS--No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 x [10.sup.-7]) and obesity in French Caucasian adult (rs4786847, P = 1.9 x [10.sup.-10]) and children (rs8054147, P = 9.2 x [10.sub.-6]) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. CONCLUSIONS--Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway. Diabetes 59:2837-2845, 2010, Recent large-scale genome-wide association studies (GWASs) have uncovered common variants in several loci associated with obesity in multiple populations (1-7). Most of these studies have been done in populations of [...]

OBJECTIVE--Genome-wide association studies that compare the statistical association between thousands of DNA variations and a human trait have detected 958 loci across 127 different diseases and traits. However, these statistical associations only provide evidence for genomic regions likely to harbor a causal gene(s) and do not directly identify such genes. We combined gene variation and expression data in a human cohort to identify causal genes. RESEARCH DESIGN AND METHODS--Global gene transcription activity was obtained for each individual in a large human cohort (n = 1,240). These quantitative transcript data were tested for correlation with genotype data generated from the same individuals to identify gene expression patterns influenced by the variants. RESULTS--Variant rs8050136 lies within intron 1 of the FTO gene on chromosome 16 and marks a locus strongly associated with type 2 diabetes and obesity and widely replicated across many populations. We report that genetic variation at this locus does not influence FTO gene expression levels (P = 0.38), but is strongly correlated with expression of RBL2 (P = 2.7 x [10.sup.-5]), ~270,000 base pairs distant to FTO. CONCLUSIONS--These data suggest that variants at FTO influence RBL2 gene expression at large genetic distances. This observation underscores the complexity of human transcriptional regulation and highlights the utility of large human cohorts in which both genetic variation and global gene expression data are available to identify disease genes. Expedient identification of genes mediating the effects of genome-wide association study-identified loci will enable mechanism-of-action studies and accelerate understanding of human disease processes under genetic influence. Diabetes 59: 726-732, 2010, The identification of genes contributing to disease development in humans will provide medical benefits in two ways. First, the defining of causative risk predisposing genetic variation will allow improvements to [...]

OBJECTIVE--SIRT1 has pleiotropic metabolic functions. We investigated whether SIRT1 genetic variation is associated with obesity. RESEARCH DESIGN AND METHODS--In 6,251 elderly subjects from the prospective, population-based Rotterdam Study, three single nucleotide polymorphisms (SNPs) in the SIRT1 gene were studied in relation to BMI and risk of obesity (BMI ≥ 30 kg/[m.sup.2]) and prospectively with BMI change after 6.4 years of follow-up. We used cross-sectional data from 2,347 participants from the Erasmus Rucphen Family (ERF) study for replication. RESULTS--Minor alleles of rs7895833 (G = 20.2%) and rs1467568 (A = 36.8%) were associated with lower BMI in the Rotterdam Study (P = 0.02 and 0.04) and in the replication cohort ERF study (P = 0.03 and 0.008) and in both studies combined (P = 0.002 for both SNPs), with a 0.2-0.4 kg/[m.sup.2] decrease in BMI per allele copy. Carriers of these alleles had 13-18% decreased risk of obesity (for rs7895833 in the Rotterdam Study: odds ratio 0.79 [95% CI 0.67-0.94], P = 0.007; in the ERF study: 0.93 [0.73-1.19], P = 0.37; and in the studies combined 0.87 [0.77-0.97], P = 0.02; for rs1467568 in the Rotterdam Study: 0.80 [0.68-0.94], P = 0.007; in the ERF study: 0.85 [0.72-0.99], P = 0.04; and in the studies combined: 0.82 [0.73-0.92], P = 0.0009). In the Rotterdam Study, the two variants were also associated with a lower BMI increase during 6.4 years of follow-up (P = 0.01 and 0.08). CONCLUSIONS--Two common variants in SIRT1 are associated with lower BMI in two independent Dutch populations. Carriers of these variants have 13-18% decreased risk of obesity and gain less weight over time. The availability of SIRT1 stimulators makes these findings relevant in light of the growing obesity epidemic. Diabetes 58:2828-2884, 2009, SIRT1 belongs to the Sirtuin protein family of nicotinamide adenine dinucleotide ([NAD.sup.+])-dependent histone deacetyleases conserved in evolution from bacteria to humans. In lower organisms such as yeast, flies, and worms, [...]

OBJECTIVE--Genetic variants in the fat mass and obesity-associated (FTO) gene have been linked with obesity and type 2 diabetes in European populations. We aimed to test the role of FTO [...]

OBJECTIVE--Kinins mediate pathophysiological processes related to hypertension, pain, and inflammation through the activation of two G-protein-coupled receptors, named [B.sub.1] and [B.sub.2]. Although these peptides have been related to glucose homeostasis, their effects on energy balance are still unknown. RESEARCH DESIGN AND METHODS--Using genetic and pharmacological strategies to abrogate the kinin [B.sub.1] receptor in different animal models of obesity, here we present evidence of a novel role for kinins in the regulation of satiety and adiposity. RESULTS---Kinin [B.sub.1] receptor deficiency in mice ([B.sub.1.sup.-/-]) resulted in less fat content, hypoleptinemia, increased leptin sensitivity, and robust protection against high-fat diet-induced weight gain. Under high-fat diet, [B.sub.1.sup.-/-] also exhibited reduced food intake, improved lipid oxidation, and increased energy expenditure. Surprisingly, [B.sub.1] receptor deficiency was not able to decrease food intake and adiposity in obese mice lacking leptin (ob/ob-[B.sub.1.sup.-/-]). However, ob/ob-[B.sub.1.sup.-/-] mice were more responsive to the effects of exogenous leptin on body weight and food intake, suggesting that [B.sub.1] receptors may be dependent on leptin to display their metabolic roles. Finally, inhibition of weight gain and food intake by [B.sub.1] receptor ablation was pharmacologically confirmed by long-term administration of the kinin [B.sub.1] receptor antagonist SSR240612 to mice under high-fat diet. CONCLUSIONS--Our data suggest that kinin [B.sub.1] receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity., According to the World Health Organization, one billion people worldwide are overweight, and at least 300 million are clinically obese (www.who.int). Besides the negative social stigma carried by obese individuals, [...]

Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01-1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2-2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 ± 6.6 vs. 28.9 ± 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01-2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with -953A, the -953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/ enhancer binding protein (C/EBP)β transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes., Obesity and related abnormalities, including type 2 diabetes and dyslipidemia, are becoming epidemic, thus representing major health care problems (1). Although these abnormalities have a clear genetic component, the involved [...]

In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 ± 4.3 vs. 1.4 ± 0.6%, P < 0.001). Typical 'crowns' of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 ± 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxiainducible factor-1α [HIF-1α]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1α may play roles in the attraction of macrophages in scWAT., Obesity is considered a chronic low-grade inflammatory disease (1). The white adipose tissue (WAT) of obese subjects is characterized by increased production and secretion of a wide panel of inflammatory [...]

Zucker fatty (fa/fa) rats exhibit overt obesity, hyper-cholesterolemia, hyperlipidemia, and hyperglycemia as recessive traits. Thefa mutation has been determined to be a missense mutation in the extracellular domain of the [...]

Relationships of maternal obesity, diabetes, and nutrition during pregnancy with birth weight and in turn relationships between birth weight and risk of obesity and diabetes in later life have long [...]

In 2009-2010, 78 million U.S. adults aged >20 years were obese--a number representing 35.7% of the adult population. As the prevalence of obesity continues its alarming rise among both adults [...]