Oxygen-Dependent Regulation of Fatty Acid Metabolism and Endoplasmic Reticulum Function in Adipocytes

Abstract

Adipose tissue plays a fundamental role in the regulation of systemic metabolism. Obesity is a chronic disease characterized by excessive accumulation of body fat resulting in various pathological alterations in adipose tissue that contribute to systemic abnormalities. Dysregulated de novo lipogenesis (DNL) and endoplasmic reticulum (ER) function are two of these major changes manifested in obese humans and mice; however, the mechanisms leading to these changes in obese adipose tissue are poorly understood. Here we demonstrate that hypoxia, a key outcome of adipocyte expansion, regulates SCD1-dependent fatty acid desaturation and ER function in adipocytes. We propose a mechanism whereby suppression of SCD1 and palmitoleate production mediates hypoxia-induced ER stress in adipocytes. In addition, we identify one of the major oxygen sensing proteins, PHD3, as a novel regulator of ER function in adipocytes and systemic glucose metabolism in obesity. These findings underscore the importance of hypoxia and PHD3-dependent oxygen sensing in the regulation of fatty acid metabolism and ER function in adipocytes. Overall, our results provide insight into the mechanisms interconnecting key obesity-associated pathologies in adipose tissue that may aid in the development of new therapeutic approaches.