Serum Vitamin D Concentrations in Baboons (Papio spp.) during Pregnancy and Obesity.

Obesity is associated with vitamin D deficiency, which can lead to serious problems during pregnancy. However, the mechanisms of the deficiency and guidelines for vitamin D supplementation during pregnancy are not established yet, and variations in environmental exposures combined with the difficulties of performing research in pregnant women are obstacles in the evaluation of vitamin D metabolism. Baboons (Papio spp.) are an excellent, well-established model for reproductive research and represent a unique opportunity to study vitamin D metabolism in a controlled environment. This study used secondary data and specimen analysis as well as a novel experimental design to evaluate pregnant and nonpregnant baboons that were or were not exposed to sunlight while they were obese and after weight reduction. Daily D3 intake was 71% higher in nonpregnant obese baboons than in their nonobese counterparts, but serum vitamin D concentrations did not differ between these populations. In addition, serum 25-hydroxyvitamin D concentrations correlated negatively with the obesity index. This report is the first to show the effect of obesity and pregnancy on vitamin D concentrations in a NHP population. These data underline the importance of adequate vitamin D supplementation in obese animals.

Vitamin D heritability and effect of pregnancy status in Vervet monkeys (Chlorocebus aethiops sabaeus) under conditions of modest and high dietary supplementation.

OBJECTIVES: The two objectives of the current study were to: 1) investigate the genetic contributions to variations in serum vitamin D concentrations under two dietary conditions (a standard monkey biscuit diet vs. a diet designed to model typical American consumption); and 2) explore the interaction of vitamin D with pregnancy status using a cohort of pedigreed female vervet/African green monkeys. METHODS: This study includes 185 female (≥3.5 years) vervet/African green monkeys (Chlorocebus aethiops sabaeus) from a multi-generational, pedigreed breeding colony. The 25(OH)D3 concentrations were first measured seven to eight weeks after consuming a "typical American" diet (TAD), deriving 37, 18, and 45% of calories from fat, protein sources, and carbohydrates, and supplemented with vitamin D to a human equivalent of 1,000 IU/day. Vitamin D concentrations were assessed again when animals were switched to a low-fat, standard biscuit diet (LabDiet 5038) for 8 months, which provided a human equivalent of approximately 4,000 IU/day of vitamin D. All statistical analyses were implemented in SOLAR. RESULTS: Pregnancy was associated with reduced 25(OH)D3 concentrations. Heritability analyses indicated a significant genetic contribution to 25(OH)D3 concentrations in the same monkeys consuming the biscuit diet (h(2) =0.66, P=0.0004) and TAD (h(2) =0.67, P=0.0078) diets, with higher 25(OH)D3 concentrations in animals consuming the biscuit diet. Additionally, there was a significant genotype-by-pregnancy status interaction on 25(OH)D3 concentrations (P<0.05) only among animals consuming the TAD diet. DISCUSSION: These results support the existence of a genetic contribution to differences in serum 25(OH)D3 concentrations by pregnancy status and emphasize the role of diet (including vitamin D supplementation) in modifying genetic signals as well as vitamin D concentrations.

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

Molecular evolution and expression profile of the chemerine encoding gene RARRES2 in baboon and chimpanzee.

BACKGROUND: Chemerin, encoded by the retinoic acid receptor responder 2 (RARRES2) gene is an adipocytesecreted protein with autocrine/paracrine functions in adipose tissue, metabolism and inflammation with a recently described function in vascular tone regulation, liver, steatosis, etc. This molecule is believed to represent a critical endocrine signal linking obesity to diabetes. There are no data available regarding evolution of RARRES2 in non-human primates and great apes. Expression profile and orthology in RARRES2 genes are unknown aspects in the biology of this multigene family in primates. Thus; we attempt to describe expression profile and phylogenetic relationship as complementary knowledge in the function of this gene in primates. To do that, we performed A RT-PCR from different tissues obtained during necropsies. Also we tested the hypotheses of positive evolution, purifying selection, and neutrality. And finally a phylogenetic analysis was made between primates RARRES2 protein. RESULTS: RARRES2 transcripts were present in liver, lung, adipose tissue, ovary, pancreas, heart, hypothalamus and pituitary tissues. Expression in kidney and leukocytes were not detectable in either species. It was determined that the studied genes are orthologous. CONCLUSIONS: RARRES2 evolution fits the hypothesis of purifying selection. Expression profiles of the RARRES2 gene are similar in baboons and chimpanzees and are also phylogenetically related.

Molecular evolution and expression profile of the chemerine encoding gene RARRES2 in baboon and chimpanzee

BACKGROUND: Chemerin, encoded by the retinoic acid receptor responder 2 (RARRES2) gene is an adipocytesecreted protein with autocrine/paracrine functions in adipose tissue, metabolism and inflammation with a recently described function in vascular tone regulation, liver, steatosis, etc. This molecule is believed to represent a critical endocrine signal linking obesity to diabetes. There are no data available regarding evolution of RARRES2 in non-human primates and great apes. Expression profile and orthology in RARRES2 genes are unknown aspects in the biology of this multigene family in primates. Thus; we attempt to describe expression profile and phylogenetic relationship as complementary knowledge in the function of this gene in primates. To do that, we performed A RT-PCR from different tissues obtained during necropsies. Also we tested the hypotheses of positive evolution, purifying selection, and neutrality. And finally a phylogenetic analysis was made between primates RARRES2 protein. RESULTS: RARRES2 transcripts were present in liver, lung, adipose tissue, ovary, pancreas, heart, hypothalamus and pituitary tissues. Expression in kidney and leukocytes were not detectable in either species. It was determined that the studied genes are orthologous. CONCLUSIONS: RARRES2 evolution fits the hypothesis of purifying selection. Expression profiles of the RARRES2 gene are similar in baboons and chimpanzees and are also phylogenetically related.

Lipoprotein subfractions and dietary intake of n-3 fatty acid: the Genetics of Coronary Artery Disease in Alaska Natives study.

BACKGROUND: Few studies have compared lipoprotein composition with dietary intake. OBJECTIVE: The lipoprotein subfraction profile was evaluated in relation to diet in Alaska Eskimos at high cardiovascular risk but with a low frequency of hyperlipidemia and high intake of n-3 (omega-3) fatty acids. DESIGN: A population-based sample (n = 1214) from the Norton Sound Region of Alaska underwent a physical examination and blood sampling. Analyses were from 977 individuals who did not have diabetes or use lipid-lowering medications and had complete dietary information (food-frequency questionnaire) and a lipoprotein subfraction profile (nuclear magnetic resonance spectroscopy). RESULTS: After adjustment for age, BMI, total energy intake, and percentage of energy from fat, the intake of n-3 fatty acids was significantly associated with fewer large VLDLs (P = 0.022 in women, P = 0.064 in men), a smaller VLDL size (P = 0.018 and P = 0.036), more large HDLs (P = 0.179 and P = 0.021), and a larger HDL size (P = 0.004 and P = 0.001). After adjustment for carbohydrate and sugar intakes, large VLDLs (P = 0.042 and 0.018) and VLDL size (P = 0.011 and 0.025) remained negatively associated with n-3 fatty acid intake in women and men, and large HDLs (P = 0.067 and 0.005) and HDL size (P = 0.001 in both) remained positively associated with n-3 fatty acid intake in women and men. In addition, large LDLs (P = 0.040 and P = 0.025) were positively associated in both sexes, and LDL size (P = 0.006) showed a positive association in women. There were no significant relations with total LDL particles in either model. CONCLUSIONS: Dietary n-3 fatty acids, independent of the reciprocal changes in carbohydrate and sugar intakes, are associated with an overall favorable lipoprotein profile in terms of cardiovascular risk. Because there are no relations with total LDL particles, the benefit may be related to cardiovascular processes other than atherosclerosis.

Heart rate is associated with red blood cell fatty acid concentration: the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.

BACKGROUND: Consumption of omega-3 fatty acids (FAs) is associated with a reduction in deaths from coronary heart disease, arrhythmia, and sudden death. Although these FAs were originally thought to be antiatherosclerotic, recent evidence suggests that their benefits are related to reducing risk for ventricular arrhythmia and that this may be mediated by a slowed heart rate (HR). METHODS: The study was conducted in Alaskan Eskimos participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study, a population experiencing a dietary shift from unsaturated to saturated fats. We compared HR with red blood cell (RBC) FA content in 316 men and 391 women ages 35 to 74 years. RESULTS: Multivariate linear regression analyses of individual FAs with HR as the dependent variable and specific FAs as covariates revealed negative associations between HR and docosahexaenoic acid (22:6n-3; P = .004) and eicosapentaenoic acid (20:5n-3; P = .009) and positive associations between HR and palmitoleic acid (16:1n-7; P = .021), eicosanoic acid (20:1n9; P = .007), and dihomo-gamma-linolenic acid (DGLA; 20:3n-6; P = .021). Factor analysis revealed that the omega-3 FAs were negatively associated with HR (P = .003), whereas a cluster of other, non-omega-3 unsaturated FAs (16:1, 20:1, and 20:3) was positively associated. CONCLUSIONS: Marine omega-3 FAs are associated with lower HR, whereas palmitoleic and DGLA, previously identified as associated with saturated FA consumption and directly related to cardiovascular mortality, are associated with higher HR. These relations may at least partially explain the relations between omega-3 FAs, ventricular arrhythmia, and sudden death.

Polyunsaturated fatty acids effect on serum triglycerides concentration in the presence of metabolic syndrome components. The Alaska-Siberia Project.

Serum fatty acids (FAs) have wide effects on metabolism: Serum saturated fatty acids (SFAs) increase triglyceride (TG) levels in plasma, whereas polyunsaturated fatty acids (PUFAs) reduce them. Traditionally, Eskimos have a high consumption of omega-3 fatty acids (omega3 FAs); but the Westernization of their food habits has increased their dietary SFAs, partly reflected in their serum concentrations. We studied the joint effect of serum SFAs and PUFAs on circulating levels of TGs in the presence of metabolic syndrome components. We included 212 men and 240 women (age, 47.9 +/- 15.7 years; body mass index [BMI], 26.9 +/- 5.3) from 4 villages located in Alaska for a cross-sectional study. Generalized linear models were used to build surface responses of TG as functions of SFAs and PUFAs measured in blood samples adjusting by sex, BMI, and village. The effects of individual FAs were assessed by multiple linear regression analysis, and partial correlations (r) were calculated. The most important predictors for TG levels were glucose tolerance (r = 0.116, P = .018) and BMI (r = 0.42, P < .001). Triglyceride concentration showed negative associations with 20:3omega6 (r = -0.16, P = .001), 20:4omega6 (r = -0.14, P = .005), 20:5omega3 (r = -0.17, P < .001), and 22:5omega3 (r = -0.26, P < .001), and positive associations with palmitic acid (r = 0.16, P < .001) and 18:3omega3 (r = 0.15, P < .001). The surface response analysis suggested that the effect of palmitic acid on TG is blunted in different degrees according to the PUFA chemical structure. The long-chain omega3, even in the presence of high levels of saturated fat, was associated with lower TG levels. Eicosapentaenoic acid (20:5omega3) had the strongest effect against palmitic acid on TG. The total FA showed moderate association with levels of TG, whereas SFA was positively associated and large-chain PUFA was negatively associated. The Westernized dietary habits among Eskimos are likely to change their metabolic profile and increase comorbidities related to metabolic disease.

[Molecular targets for new drug discovery to treat type 2 diabetes and obesity]. / Objetivos moleculares para diseñar nuevos fármacos para el tratamiento de la diabetes tipo 2 y la obesidad.

Current strategies to treat type 2 diabetes (DMT2) include reducing insulin resistance using glitazones, supplementing with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of molecules with improved efficacy and safety profiles, are being investigated. Promising biological targets are rapidly emerging such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, recombinant adiponectin derivatives, and fatty acid synthase (FAS) inhibitors. Insulin action can be enhanced in muscle, liver and fat, with small-molecule activators of the insulin receptor or inhibitors of protein tyrosine phosphatase (FTP)-IB. Defective glucose-stimulated insulin secretion by pancreatic B-cells could be alleviated with recombinant glucagon-like peptide (GLP-1) or agonists to the GLP-1 receptor. This review presents a new approach for obesity and DMT2 drug discovery through pharmacogenomics. Several compounds have already been validated through genetic engineering in animal models or the preliminary use of therapeutic compounds in humans.

Objetivos moleculares para diseñar nuevos fármacos para el tratamiento de la diabetes tipo 2 y la obesidad: [revisión] / Molecular targets for new drug discovery to treat type 2 diabetes and obesity: [review]

Current strategies to treat type 2 diabetes (DMT2) include reducing insulin resistance using glitazones, supplementing with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of molecules with improved efficacy and safety profiles, are being investigated. Promising biological targets are rapidly emerging such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, recombinant adiponectin derivatives, and fatty acid synthase (FAS) inhibitors. Insulin action can be enhanced in muscle, liver and fat, with small-molecule activators of the insulin receptor or inhibitors of protein tyrosine phosphatase (FTP)-IB. Defective glucose-stimulated insulin secretion by pancreatic B-cells could be alleviated with recombinant glucagon-like peptide (GLP-1) or agonists to the GLP-1 receptor. This review presents a new approach for obesity and DMT2 drug discovery through pharmacogenomics. Several compounds have already been validated through genetic engineering in animal models or the preliminary use of therapeutic compounds in humans.

Consumption of omega-3 fatty acids is not associated with a reduction in carotid atherosclerosis: the Genetics of Coronary Artery Disease in Alaska Natives study.

OBJECTIVE: This study was designed to evaluate the relation between omega-3 fatty acid (FA) consumption and atherosclerosis. BACKGROUND: The hypothesis that omega-3 FAs protect against atherosclerosis has not been tested with objective measures of atherosclerosis. METHODS: A population-based sample of 1131 Alaskan Eskimos of age >or=18 underwent ultrasound assessment of carotid atherosclerosis. Those of age >35 (N=686) were included in the analysis. Diet was assessed by a food frequency questionnaire. Intimal-medial thickness (IMT) of the far wall of the distal common carotid arteries and plaque score (number of segments containing plaque) were assessed. RESULTS: Mean consumption of total omega-3 FAs was 4.76 g/day in those without and 5.07 g/day in those with plaque. In models adjusting for relevant risk factors, presence and extent of plaque were unrelated to intake of C20-22 omega-3 FAs or total omega-3 FAs. In contrast, the odds of plaque rose significantly with quartiles of palmitic (p=0.02) and stearic acid intake (p=0.04). The extent of plaque (or plaque score) was also associated with a higher percentage intake of palmitic acid (p=0.01). IMT was negatively associated with grams of C20-22 omega-3 FAs (p=0.05), total omega-3 (p=0.05), palmitate (p=0.03), and stearate (p=0.03) consumed. CONCLUSIONS: Dietary intake of omega-3 FAs in a moderate-to-high range does not appear to be associated with reduced plaque, but is negatively associated with IMT. The presence and extent of carotid atherosclerosis among Eskimos is higher with increasing consumption of saturated FAs.

Fatty acid consumption and metabolic syndrome components: the GOCADAN study.

Fatty acids (FAs) have been related to changes in glucose and lipid metabolism. In this article, the authors assess the association between intake of specific FAs and components of the metabolic syndrome (MS) in adult Eskimos. A total of 691 Inupiat Eskimos (325 men and 366 women), aged 34 to 75 years, were examined as part of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. The investigation included a physical examination, blood pressure measurements, blood sampling under fasting conditions, 2-hour oral glucose tolerance test, and a personal interview including a validated food frequency questionnaire. Components of MS were defined according to the Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria. Consumption of individual FAs showed associations with MS components. Long-chain omega-3 FAs, from fish and sea mammals, were associated with lower blood pressure, serum triglycerides, and 2-hour glucose and higher high-density lipoprotein cholesterol, fasting insulin, and homeostasis model assessment. Saturated fat consumption was associated with higher triglyceride levels and blood pressure. Trans-FA consumption was associated with higher blood pressure. Consumption of long-chain omega-3 FAs from marine sources may improve certain MS components, and thus may reduce risk for cardiovascular disease. High consumption of saturated FAs and trans-FAs may have an adverse effect on MS.