Fish Oil Supplementation Ameliorates Fructose-Induced Hypertriglyceridemia and Insulin Resistance in Adult Male Rhesus Macaques

Departments of Pediatrics, and.
Journal of Nutrition (Impact Factor: 4.23). 10/2013; 144(1). DOI: 10.3945/jn.113.178061
Source: PubMed

ABSTRACT Fish oil (FO) is a commonly used supplemental source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2 n-3 (ω-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a variety of health benefits considered to be protective against cardiometabolic diseases. Although the effects of EPA and DHA on lipid metabolism have been extensively studied, not all of the metabolic effects of FO-derived n-3 PUFAs have been characterized. Our laboratory recently showed that a high-fructose diet in rhesus monkeys induces the features of metabolic syndrome (MetS) similar to those observed in humans. Thus, we specifically wanted to evaluate the effects of FO in rhesus monkeys fed a high-fructose diet and hypothesized that FO supplementation would mitigate their development of fructose-induced insulin resistance, dyslipidemia, and other cardiometabolic risk factors. In this study, adult monkeys (aged 12-20 y) received either standard chow plus 75 g fructose/d (control group; n = 9) or standard chow, 75 g fructose/d, and 4 g FO (16% EPA/11% DHA)/d (treatment group; n = 10) for 6 mo. Importantly, our results showed that daily FO supplementation in the monkeys prevents fructose-induced hypertriglyceridemia and insulin resistance as assessed by intravenous-glucose-tolerance testing (P ≤ 0.05). Moreover, FO administration in the monkeys prevented fructose-induced increases in plasma apolipoprotein (apo) C3, apo E, and leptin concentrations and attenuated decreases in circulating adropin concentrations (P ≤ 0.05). No differences between the control and FO-treated monkeys were observed in body weight, lean mass, fat mass, or fasting glucose, insulin, and adiponectin concentrations. In conclusion, FO administration in a nonhuman primate model of diet-induced MetS ameliorates many of the adverse changes in lipid and glucose metabolism induced by chronic fructose consumption.

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    ABSTRACT: Background An important inter-individual variability in the response of insulin sensitivity following a fish oil supplementation has been observed. The objective was to examine the associations between single nucleotide polymorphisms (SNPs) within sterol regulatory element binding transcription factor 1 (SREBF1) gene and the response of insulin sensitivity to a fish oil supplementation. Methods Participants (n = 210) were recruited in the greater Quebec City area and followed a 6-week fish oil supplementation protocol (5 g/day: 1.9-2.2 g EPA; 1.1 g DHA). Insulin sensitivity was assessed by the quantitative insulin sensitivity check index (QUICKI). Three tag SNPs (tSNPs) within SREBF1 gene were genotyped according to TAQMAN methodology. Results Three tSNPs (rs12953299, rs4925118 and rs4925115) covered 100% of the known genetic variability within SREBF1 gene. None of the three tSNPs was associated with either baseline fasting insulin concentrations (rs12953299, rs4925118 and rs4925115) (p = 0.29, p = 0.20 and p = 0.70, respectively) or QUICKI (p = 0.20, p = 0.18 and p = 0.76, respectively). The three tSNPs (rs12953299, rs4925118 and rs4925115) were associated with differences in the response of plasma insulin levels (p = 0.01, p = 0.005 and p = 0.004, respectively) and rs12953299 as well as rs4925115 were associated with the insulin sensitivity response (p = 0.009 and p = 0.01, respectively) to the fish oil supplementation, independently of the effects of age, sex and BMI. Conclusions The genetic variability within SREBF1 gene has an impact on the insulin sensitivity in response to a fish oil supplementation. Trial registration NCT01343342.
    Lipids in Health and Disease 10/2014; 13(1):152. DOI:10.1186/1476-511X-13-152 · 2.31 Impact Factor
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    ABSTRACT: Despite compelling evidence that oxytocin (OT) is effective in reducing body weight (BW) in diet-induced obese (DIO) rodents, studies of the effects of OT in humans and rhesus monkeys have primarily focused on non-ingestive behaviors. The goal of this study was to translate findings in DIO rodents to a pre-clinical translational model of DIO. We tested the hypothesis that increased OT signaling would reduce BW in DIO rhesus monkeys by inhibiting food intake and increasing energy expenditure (EE). Male DIO rhesus monkeys from the California National Primate Research Center were adapted to a 12-h fast and maintained on chow and a daily 15% fructose-sweetened beverage. Monkeys received 2x daily subcutaneous vehicle injections over 1 week. We subsequently identified doses of OT (0.2 and 0.4 mg/kg) that reduced food intake and BW in the absence of nausea or diarrhea. Chronic administration of OT for 4 weeks (0.2 mg/kg for 2 weeks; 0.4 mg/kg for 2 weeks) reduced BW relative to vehicle by 3.3±0.4% (≈0.6 kg; P<0.05). Moreover, the low dose of OT suppressed 12-h chow intake by 26±7% (P<0.05). The higher dose of OT reduced 12-h chow intake by 27±5% (P<0.05) and 8-h fructose-sweetened beverage intake by 18±8 % (P<0.05). OT increased EE during the dark cycle by 14±3% (P<0.05) and was associated with elevations of free fatty acids and glycerol and reductions in triglycerides suggesting increased lipolysis. Together, these data suggest that OT reduces BW in DIO rhesus monkeys through decreased food intake as well as increased EE and lipolysis. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 12/2014; DOI:10.1152/ajpregu.00441.2014 · 3.53 Impact Factor
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    ABSTRACT: The peptide hormone adropin regulates fuel selection preferences in skeletal muscle under fed and fasted conditions. Here, we investigated whether adropin treatment can ameliorate the dysregulation of fuel substrate metabolism, and improve aspects of glucose homeostasis in diet-induced obesity (DIO) with insulin resistance. DIO C57BL/6 mice maintained on a 60% kcal fat diet received five intraperitoneal (i.p.) injections of the bioactive peptide adropin(34-76) (450 nmol/kg/i.p.). Following treatment, glucose tolerance and whole body insulin sensitivity were assessed and indirect calorimetry was employed to analyze whole body substrate oxidation preferences. Biochemical assays performed in skeletal muscle samples analyzed insulin signaling action and substrate oxidation. Adropin treatment improved glucose tolerance, enhanced insulin action and augmented metabolic flexibility towards glucose utilization. In muscle, adropin treatment increased insulin-induced Akt phosphorylation and cell-surface expression of GLUT4 suggesting sensitization of insulin signaling pathways. Reduced incomplete fatty acid oxidation and increased CoA/acetyl-CoA ratio suggested improved mitochondrial function. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activated pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulated PDH kinase-4 (PDK-4) that inhibits PDH. Along with these changes, adropin treatment downregulated peroxisome proliferator-activated receptor-gamma coactivator-1α that regulates expression of Cpt1b, Cd36 and Pdk4. Adropin treatment of DIO mice enhances glucose tolerance, ameliorates insulin resistance and promotes preferential use of carbohydrate over fat in fuel selection. Skeletal muscle is a key organ in mediating adropin's whole-body effects, sensitizing insulin signaling pathways and altering fuel selection preference to favor glucose while suppressing fat oxidation.
    04/2015; 4:310-324. DOI:10.1016/j.molmet.2015.01.005


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Sep 11, 2014