Thermoneutrality Reduces the Beneficial Metabolic Effects of Eicosapentaenoic Acid on White Adipose Tissue in Diet-Induced Obese Mice

Abstract

Abstract Objectives At ambient temperature (23°C), eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid reduces visceral adipose tissue (VAT) inflammation, adipocyte size and improves overall metabolic profile in diet-induced obese (DIO) mice, potentially through upregulation of uncoupling protein 1 (UCP-1). The goal of this study is to determine whether effects of EPA are maintained at thermoneutrality, and/or mediated by UCP-1, and if so through which cellular mechanisms. Methods Wild type (WT) and UCP-1 knockout (KO) B6 male mice were housed at thermoneutral temperature (28–30°C) and fed high fat (HF, 45% kcal fat) supplemented with or without EPA (36 g/kg diet). Serum, VAT (epididymal fat) and cecal microbiome specimens were analyzed. Results EPA reduced adiposity and improved glucose tolerance in EPA-fed KO mice (P < 0.05), but not in EPA-fed WT mice. EPA supplementation lowered VAT mass in both genotypes (P < 0.05); however, there were no diet or genotype-related differences in adipocyte size or serum triglyceride levels. Both genotypes fed EPA had lower serum resistin levels compared to respective HF (P < 0.01). EPA showed trends towards increased serum adiponectin levels compared to HF fed mice in both genotypes, with KO-EPA group having the highest concentration. There was no significant difference in the expression of IL-6 in VAT among the groups, while MCP-1 mRNA was expressed more in KO groups compared to WT groups (P < 0.01). Diet had no effect on expression of anti-inflammatory markers in both WT and KO mice. There were no genotype or diet effects on expression of genes involved in lipid metabolism and mitochondrial energy metabolism. Cecal microbiome showed no differences in the species diversity (Shannon index) between genotypes or diet types. However, only in the KO group, the Bacteroidetes/Firmicutes ratio was increased by EPA. Conclusions Compared to previous work at ambient temperatures, VAT does not mediate protective effects of EPA in DIO mice at thermoneutral temperature. Moreover, EPA effects are independent of UCP-1 as it produced beneficial effects on glucose tolerance and adiposity in KO mice, which may be in part mediated by changes in microbiome. Further mechanistic studies are ongoing to understand the mechanisms mediating EPA and UCP-1 effects in VAT. Funding Sources Funded by NIH (NCCIH and NIA).