PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.

The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease.

High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.

Obesity is generally recognized as a condition which positively influences bone mass and bone mineral density (BMD). Positive effect of high body mass index (BMI) on bone has been recognized as a result of increased mechanical loading exerted on the skeleton. However, epidemiologic studies indicate that obesity is associated with increased incidence of fractures. The results presented here offer a new perspective regarding the mechanisms which may be responsible for the increase of bone mass and concurrent decrease in bone quality. Two groups of 12 week old C57BL/6 males were fed either high fat diet (HFD) or regular diet (RD) for 11 weeks. Metabolic profile, bone parameters and gene expression were assessed in these groups at the end of the experiment. Additionally, bone status was evaluated in a third group of 12 week old animals corresponding to animals at the start of the feeding period. Administration of HFD resulted in development of a diet-induced obesity (DIO), glucose intolerance, alteration in energy metabolism, and impairment in WAT function, as compared to the age-matched control animals fed RD. The expression of adiponectin, FABP4/aP2, DIO2 and FoxC2 were decreased in WAT of DIO animals, as well as transcript levels for IGFBP2, the cytokine regulating both energy metabolism and bone mass. At the end of experiment, DIO mice had higher bone mass than both control groups on RD, however they had decreased bone formation, as assessed by calcein labeling, and increased marrow adipocyte content. This study suggests that the bone mass acquired in obesity is a result of a two-phase process. First phase would consist of either beneficial effect of fat expansion to increase bone mass by increased mechanical loading and/or increased production of bone anabolic adipokines and/or nutritional effect of fatty acids. This is followed by a second phase characterized by decreased bone formation and bone turnover resulting from development of metabolic impairment.

PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats.

OBJECTIVE: Renin-angiotensin system (RAS) regulates adipogenic response with adipocyte hypertrophy by increasing oxidative stress. Recent studies have shown the role of peroxisome proliferator-activated receptor-δ (PPARδ) agonist in attenuation of angiotensin II-induced oxidative stress. The aim of this study was to explore a potential mechanistic link between PPARδ and the cytoprotective enzyme heme oxygenase-1 (HO-1) and to elucidate the contribution of HO-1 to the adipocyte regulatory effects of PPARδ agonism in an animal model of enhanced RAS, the Goldblatt 2 kidney 1 clip (2K1C) model. METHOD: We first established a direct stimulatory effect of the PPARδ agonist (GW 501516) on the HO-1 gene by demonstrating increased luciferase activity in COS-7 cells transfected with a luciferase-HO-1 promoter construct. Sprague-Dawley rats were divided into four groups: sham-operated animals, 2K1C rats and 2K1C rats treated with GW 501516, in the absence or presence of the HO activity inhibitor, stannous mesoporphyrin (SnMP). RESULTS: 2K1C animals had increased visceral adiposity, adipocyte hypertrophy, increased inflammatory cytokines, increased circulatory and adipose tisssue levels of renin and Ang II along with increased adipose tissue gp91 phox expression (P<0.05) when compared with sham-operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (P<0.01) along with enhancement of Wnt10b and ß-catenin expression. HO-1 induction was accompanied by the decreased expression of Wnt5b, mesoderm specific transcript (mest) and C/EBPα levels and an increased number of small adipocytes (P<0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (P<0.05). CONCLUSION: Taken together, our study demonstrates, for the first time, that increased levels of Ang II contribute towards adipose tissue dysregulation, which is abated by PPARδ-mediated upregulation of the heme-HO system. These findings highlight the pivotal role and symbiotic relationship of HO-1, adiponectin and PPARδ in the regulation of metabolic homeostasis in adipose tissues.