3029-LB: Activation of the Malate–Aspartate Shuttle in Brown Adipose Tissue Improves Glucose Homeostasis in Diet-Induced Obesity

Introduction and Objective: The malate-aspartate shuttle (MAS) is a key redox system that transfers cytosolic reducing equivalents (e.g., NADH) produced during glycolysis into mitochondria, thereby maintaining cellular NAD+/NADH homeostasis. MAS activity relies on two mitochondrial carriers and paired cytosolic and mitochondrial enzymes (GOT1/2 and MDH1/2). Unlike abundant expression of MAS enzymes in other tissues, GOT1 in brown adipose tissue (BAT) is robustly induced by cold exposure from near-undetectable baseline levels, while other MAS enzymes are constitutively expressed. We previously demonstrated that GOT1-driven MAS activation in BAT (R26-Got1BATOE/+ mice) enhances glucose uptake, glycolytic flux, and mitochondrial fatty acid oxidation, thereby improving cold tolerance. The objective of this study was to determine whether MAS activation in BAT influences metabolic homeostasis under obese conditions. Methods: R26-Got1fl/+ and R26-Got1BATOE/+ mice (n=8 per group) were fed a high-fat diet (45% kcal from fat) for 9 weeks and weekly monitored for body weight and food intake throughout the feeding period. At the end of the study, glucose and insulin tolerance tests were performed to assess blood glucose regulation. Results: Both genotypes exhibited comparable weight gain and food intake during HFD feeding. Consistent with enhanced BAT glucose uptake, R26-Got1BATOE/+ mice displayed modestly improved glucose clearance during a glucose tolerance test, while systemic insulin sensitivity remained unchanged. Conclusion: Together, these data indicate that MAS activation in BAT improves glucose homeostasis in diet-induced obesity, independent of changes in body weight or insulin sensitivity. Disclosure C. Park: None. J. Chang: None. Funding National Institutes of Health (R01DK136536)