HIF1α controls adipose tissue growth through metabolic rechanneling

Abstract

Excessive expansion of white adipose tissue occurs when energy intake exceeds demand. It creates a state of relative hypoxia that is directly linked to activation of the hypoxia-inducible factor (HIF) in obese human subjects and mouse models of obesity. Whether HIF1 function is important for the development of basal adiposity and diet-induced obesity remains unclear. In the present study, we genetically ablated Hif1 in adipocytes and analyzed the corresponding mice for both basal and diet-induced obesity-associated visceral white adipose tissue mass as well as parameters of systemic glucose homeostasis and peripheral insulin sensitivity. We found that inactivation of Hif1 in mouse adipocytes inhibited basal adiposity and suppressed nutrient-overload-induced adipose tissue growth. These changes in adiposity were associated with improved systemic glucose homeostasis and peripheral insulin sensitivity. Mechanistically, Hif1 mediated effects on adipocyte metabolism by re-routing glycolytic intermediates into the glycerolipid shunt, leading to increased de novo triacylglyceride synthesis in hypertrophic adipocytes. Our results have established key roles for HIif1 in controlling adipocyte growth and metabolism and adipose tissue expansion under basal conditions and in response to a high-fat diet, highlighting the central role of hypoxia and HIF1 in the development of obesity. Article HighlightsO_LIHif1 function is critical for basal adipose tissue mass expansion, and is also required for fat accumulation in response to high fat diet. C_LIO_LICo-option and co-activation of the glycerolipid biosynthetic pathway by glycolysis is an important modulator of visceral adiposity. C_LIO_LIThese findings reveal an important role of Hif1 in the adipose tissue through the coupling of glycolysis and lipid anabolism in response to HFD, which may provide a potential therapeutic target for type 2 diabetes in the future. C_LI