HIF1α reinforces PPARγ-dependent metabolic rechanneling to support lipid accumulation in adipocytes.

INTRODUCTION: Adipose tissue hypoxia is a hallmark of obesity and partly contributes to metabolic dysfunction through effects on differentiated adipocytes. Although hypoxia-inducible factor 1α (HIF1α) is a key transcriptional mediator of hypoxic responses, its state-dependent metabolic role remains incompletely defined in mature adipocytes. Herein, we investigate how HIF1α regulates lipid metabolism in differentiated adipocytes under nutrient excess conditions. METHODS: An adipocyte-specific Hif1α knockout mouse model was subjected to high-fat diet feeding in vivo. Adipose mass, adipocyte size, glucose tolerance, and insulin sensitivity were assessed. Metabolic and enzymatic analyses focused on lipid anabolic pathways, including glycolysis-linked glycerolipid biosynthesis and PPARγ-dependent programs. RESULTS: Adipocyte-specific deletion of Hif1α attenuated adipocyte hypertrophy, resulting in reduced adipose mass as well as improved systemic glucose tolerance and insulin sensitivity during high-fat diet feeding. Mechanistically, HIF1α reinforced PPARγ-dependent lipid anabolic programs by coordinating glycolytic flux with glycerolipid biosynthesis to promote the rechanneling of glucose-derived intermediates into triacylglyceride synthesis. DISCUSSION: Together, these findings provide metabolic and enzymatic validations of a late-stage, state-dependent HIF1α-PPARγ lipid storage program and implicate the glycerol-3-phosphate dehydrogenase 1 (GPD1)-glycerol-3-phosphate acyltransferase (GPAT) axis as a key molecular executor of hypertrophic lipid accumulation in differentiated adipocytes.