PPARγ: a circadian transcription factor in adipogenesis and osteogenesis

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPAR gamma in skeletal metabolism as well. PPAR gamma agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu-that is, increased bone marrow adiposity with suppression of osteogenesis-could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPAR gamma at the center of a regulatory loop between circadian networks and metabolic output. PPAR gamma exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPAR gamma activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPAR gamma and have increased bone mass. This Review focuses on new findings regarding the role of PPAR gamma in adipose tissue and skeletal metabolism and summarizes the emerging role of PPAR gamma as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.