OBJECTIVE—To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance.

Background: Obesity is generally accompanied by increased food intake. Objective: We sought to identify the genes influencing variation in dietary macronutrient intakes in Mexican Americans. Design: We conducted a genome-wide scan by using data derived from food-frequency questionnaires in 816 participants from the San Antonio Family Heart Study. Household effect was simultaneously estimated in a variance component model with the use of SOLAR. Results: All dietary intake measures (total calories, proteins, fat, saturated fat, monounsaturated fat, polyunsaturated fat, carbohydrates, and sucrose) were moderately heritable. Household effect was insignificant except on total calories and sucrose. Suggestive evidence of linkage with saturated fat intake was found on chromosome 2p22 near marker D2S1346 [logarithm of odds (LOD) = 2.62]. Intakes of total calories, fat, protein, and monounsaturated fat were also suggestively linked to the same marker. A significant linkage signal on chromosome 2p22 for leptin concentrations and fat mass was localized in this population, so we used leptin or fat mass as a covariate. Multipoint LOD scores for saturated fat dropped to 1.27 and 1.90, respectively, which suggested that this region on chromosome 2p contributes to both saturated fat intake and body adiposity. This chromosomal region contains the proopiomelanocortin gene (POMC). However, 2 polymorphisms in exon 3 of the POMC gene showed no association with saturated fat intake. Conclusions: The results strengthen the hypothesis that chromosome 2p22 harbors genes that influence a variety of obesity-related phenotypes, including macronutrient intakes.

Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

Background: Baboons (Papio hamadryas Sp.) develop features of the cardiometabolic syndrome and represent a clinically-relevant animal model in which to study the aetiology of the disorder. To further evaluate the baboon as a model for the study of the cardiometabolic syndrome, we developed a high sugar high fat diet and hypothesized that it could be used to induce adiposity gain and affect associated circulating biomarkers. Methods: We developed a diet enriched with monosaccharides and saturated fatty acids that was composed of solid and liquid energy sources. We provided a group of baboons (n = 9) ad libitum access to this diet for 8 weeks. Concurrently, a control group (n = 6) was maintained with ad libitum access to a low sugar low fat baseline diet and normal water for 8 weeks. Body composition was determined by dual-energy X-ray absorptiometry and circulating metabolic biomarkers were measured using standard methodology before and after the 8 week study period. Results: Neither body composition nor circulating biomarkers changed in the control group. Following the 8 weeks, the intervention group had a significant increase in fat mass (1.71 ± 0.98 vs. 3.23 ± 1.70 kg, p = 0.004), triglyceride (55 ± 13 vs. 109 ± 67 mg/dL, p = 0.006,), and leptin (1.19 ± 1.40 vs. 3.29 ± 2.32 ng/mL, p = 0.001) and a decline in adiponectin concentrations (33530 ± 9744 vs. 23330 ± 7863 ng/mL, p = 0.002). Percentage haemoglobin A_1C (4.0 ± 0.3 vs. 6.0 ± 1.4, p = 0.002) also increased in the intervention group. Conclusions: Our findings indicate that when exposed to a high sugar high fat diet, young adult male baboons develop increased body fat and triglyceride concentrations, altered adipokine concentrations, and evidence of altered glucose metabolism. Our findings are in keeping with observations in humans and further demonstrate the potential utility of this highly clinically-relevant animal model for studying diet-induced metabolic dysregulation.