PPARγ: a circadian transcription factor in adipogenesis and osteogenesis

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ 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 PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ 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 PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.

Figure 1. Schematic model of the role of PPARγ in bone marrow

PPARγ regulates the specification of mesenchymal stem cells (MSCs) toward the adipogenic lineage and activation of PPARγ by specific ligands leads to increased marrow adiposity. The role of PPARγ in osteoclast differentiation is still controversial and needs to be clarified. Marrow adipocytes produce a number of secretory factors and PPARγ regulates the expression of these genes. Such factors could have a significant role in osteoblast differentiation and /or function. In pathogenic conditions, these determinants could impact osteoblasts in a negative direction, whereas in physiological conditions these factors may have a different role from the one observed in the pathogenic conditions. There is also an evidence of the role for marrow adipocytes as an inhibitory factor for hematopoiesis. PPARγ: Peroxisome proliferator-activated receptor-gamma. C/EBP: CCAAT enhancer binding protein. Runx2: Runt-related transcription factor 2. Msx2: Muscle segment homeobox homolog of 2.

Figure 2. Nocturnin regulates PPARγ circadian profile and activity

Circadian-regulated gene, Nocturnin, which is induced by external cues such as aging, high-fat diet (HFD) and insulin regulates the circadian expression pattern of PPARγ. In addition, nocturnin enhances the PPARγ transcriptional activity in part by stimulating the nuclear translocation of PPARγ. Enhanced activity of PPARγ by nocturnin may result in increased marrow adiposity and bone loss. White bar and black bar represents light and dark cycle, respectively. Noc: nocturnin, PPARγ: Peroxisome proliferator-activated receptor-gamma. RXRα : Retinoid X receptor alpha. MSCs: nesenchymal stem cells.