Peroxisome Proliferator-Activated Receptor γ and Its Role in Adipocyte Homeostasis and Thiazolidinedione-Mediated Insulin Sensitization

Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor gamma(PPAR gamma) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPAR gamma in mature adipocytes in vivo. Short-term PPAR gamma deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are viable both in vitro and in vivo. However, after exposure to a high-fat diet, even short-term PPAR gamma deficiency leads to rapid adipocyte death. When mature adipocytes are depleted of both PPAR gamma and CCAAT-enhancer-binding protein gamma(C/EBP gamma), they are rapidly depleted of lipids and undergo adipocyte death, both in vitro and in vivo. Surprisingly, although thiazolidinediones (TZDs; PPAR gamma agonists) are thought to act mainly on PPAR gamma, PPAR gamma in adipocytes is not required for the whole-body insulin-sensitizing effect of TZDs. This offers new mechanistic aspects of PPAR gamma/TZD action and its effect on whole-body metabolic homeostasis.