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

Stephen R. Farmer,Hong Wang,Li Qiang,Meghan E. McDonald,Elizabeth Pino

doi:10.1074/jbc.m112.350918

Abstract

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 1α (HIF-1α) 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-1α, but its presence alone was incapable of inducing target gene expression under normoxic conditions. In addition to the HIF-1α targets, hypoxia also induced many inflammatory genes. Exposure of white adipocytes to a peroxisome proliferator-activated receptor γ (PPARγ) ligand (troglitazone) attenuated induction of these genes but enhanced expression of the HIF-1α targets. Knockdown of PPARγ in mature white adipocytes prevented the usual robust induction of HIF-1α targets in response to hypoxia. Similarly, knockdown of PPARγ coactivator (PGC) 1β in PGC-1α-deficient brown adipocytes eliminated their response to hypoxia. These data demonstrate that the response of white adipocytes requires HIF-1α but also depends on PPARγ in white cells and the PPARγ cofactors PGC-1α and PGC-1β in brown cells.

Highlights

What are the mechanisms regulating compensatory responses to hypoxia in adipocytes? Results: Induction of hypoxia genes requires HIF-1␣ and PPAR␥ in white adipocytes and PGC-1 cofactors in brown adipocytes
Because of the fact that brown adipose tissue (BAT) is highly vascularized compared with avascular white adipose tissue (WAT), we hypothesized that brown adipocytes might respond more favorably to hypoxia than white cells by stimulating production of greater quantities of HIF-1␣
Recent studies have suggested that white adipocytes respond poorly to hypoxia due to their inability to activate HIF-1␣-associated compensatory angiogenesis (1, 2)

Summary

Background

What are the mechanisms regulating compensatory responses to hypoxia in adipocytes? Results: Induction of hypoxia genes requires HIF-1␣ and PPAR␥ in white adipocytes and PGC-1 cofactors in brown adipocytes. The response of white adipocytes to hypoxia required HIF-1␣, but its presence alone was incapable of inducing target gene expression under normoxic conditions. Recent investigations have suggested that enhanced production of fibrotic proteins, including components of a connective tissue extracellular matrix in obese WAT, is due to the accompanying hypoxia, possibly through the major hypoxia-inducible transcription factor, HIF-1␣ (1). The results show that the response of white adipocytes to low oxygen requires HIF-1␣, but its stabilization under normoxic conditions (pseudo-hypoxia) is incapable of inducing target gene expression. Treatment of white adipocytes with troglitazone attenuates inflammatory gene expression but enhances expression of the HIF-1␣ targets in response to low O2 These responses to hypoxia require peroxisome proliferator-activated receptor ␥ (PPAR␥) in white adipocytes and the PPAR␥ coactivators PGC-1␣ and PGC-1␤ in brown adipocytes

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION