Roles for Peroxisome Proliferator-activated Receptor γ (PPARγ) and PPARγ Coactivators 1α and 1β in Regulating Response of White and Brown Adipocytes to Hypoxia

Obese white adipose tissue is hypoxic but is incapable of inducing compensatory angiogenesis. Brown adipose tissue is highly vascularized, facilitating delivery of nutrients to brown adipocytes for heat production. In this study, we investigated the mechanisms by which white and brown adipocytes respond to hypoxia. Brown adipocytes produced lower amounts of hypoxia-inducible factor 1 alpha (HIF-1 alpha) than white adipocytes in response to low O-2 but induced higher levels of hypoxia-associated genes. The response of white adipocytes to hypoxia required HIF-1 alpha, but its presence alone was incapable of inducing target gene expression under normoxic conditions. In addition to the HIF-1 alpha targets, hypoxia also induced many inflammatory genes. Exposure of white adipocytes to a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand (troglitazone) attenuated induction of these genes but enhanced expression of the HIF-1 alpha targets. Knockdown of PPAR gamma in mature white adipocytes prevented the usual robust induction of HIF-1 alpha targets in response to hypoxia. Similarly, knockdown of PPAR gamma coactivator (PGC) 1 beta in PGC-1 alpha-deficient brown adipocytes eliminated their response to hypoxia. These data demonstrate that the response of white adipocytes requires HIF-1 alpha but also depends on PPAR gamma in white cells and the PPAR gamma cofactors PGC-1 alpha and PGC-1 beta in brown cells.