Effects of Eicosapentaenoic Acid on the Glycerophosphate Shuttle-Regulated Inflammatory and Thermogenic Responses

Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a crucial enzyme in the glycerophosphate shuttle, linking glycolysis, lipogenesis, and oxidative phosphorylation, making it a potential target for obesity treatment. Given the metabolic benefits of eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, we hypothesized that EPA modulates the GPD2-centered glycerophosphate shuttle to reduce adiposity, glucose intolerance, and inflammation while increasing energy expenditure.

Male and female GPD2 knockout (KO) and wild-type (WT) littermates were fed a high-fat diet (HF) without or with an 18 g EPA/kg (EPA) diet for 13 weeks. Body weight, glucose tolerance, and metabolic profiles were assessed, and blood and tissues were collected following euthanasia.

Male GPD2 KO mice exhibited reduced adiposity and lower lipid accumulation in hepatic and adipose tissues compared to WT males. These effects were linked to lipid metabolism and beige fat activation. EPA supplementation reduced body weight and promoted glucose clearance in both WT and KO males, with enhanced hepatic lipid oxidation. However, GPD2 deficiency and EPA had minimal metabolic effects in females.

Our findings highlight potential mechanisms by which GPD2 combats obesity by mediating lipid metabolism. Our findings further demonstrate the sex-dependent nature of EPA's metabolic benefits, independent of GPD2 deficiency.