Effects of Eicosapentaenoic Acid in Glycerol Phosphate Shuttle GPD2 Regulated Inflammatory and Thermogenic Responses

Abstract

Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is crucial enzyme in the glycerophosphate shuttle, linking glycolysis, lipogenesis, and oxidative phosphorylation, making it a potential target for obesity treatment. We previously found that eicosapentaenoic acid (EPA), an omega-3 fatty acid, increased fatty acid oxidation and GPD2 expression in uncoupling protein 1 (UCP1) deficient mice. Here, utilizing Gpd2 knockout (KO) mice, we hypothesized that EPA mediates GPD2-centered glycerophosphate shuttle to reduce diet-induced adiposity, glucose intolerance, and inflammation while boosting energy expenditure. After 13 weeks high fat diet intervention without (HF) or with an 18g EPA/kg (EPA), male GPD2 KO mice exhibited decreased adiposity, insulin resistance, and hepatic and adipose lipid accumulation compared to wild-type (WT) mice. These effects were linked to increased energy expenditure and beige fat activation. Compared to HF diet, EPA supplementation reduced body weight and promoted glucose clearance in male both WT and KO mice, with enhanced expression of hepatic lipid oxidative genes. However, GPD2 deficiency and EPA had less impact on these metabolic phenotypes in females. Our findings highlight the potential mechanisms by which GPD2 combats obesity and related disorders by mediating energy expenditure. Our findings also demonstrate the sex-dependent nature of EPA’s metabolic benefits, independently of GPD2 deficiency.