Partial agonist, telmisartan, maintains PPARγ serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass.

Vipula Kolli,Beata Lecka-Czernik,Sima Rahman,Abigail R Dowling,Lance A Stechschulte,Piotr J Czernik,Pierre J Marie

doi:10.1371/journal.pone.0096323

Abstract

Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced “browning” of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat “browning” activity and a lack of anti-osteoblastic activity.

Highlights

Peroxisome proliferator activated receptor gamma (PPARc) belongs to a family of DNA-binding nuclear receptors and functions as an adipocyte-specific transcription factor and a key regulator of cellular insulin sensitivity [1]
TEL activity as PPARc agonist and its effect on marrow mesenchymal stem cells (MSCs) differentiation was tested in a model of U-33/c2 cells where differentiation toward osteoblasts and adipocytes is under control of PPARc2 isoform
Consistent with a weaker adipocytic activity, the levels of expression of phenotypespecific gene markers including fatty acids binding protein 4 (FABP4/aP2), adiponectin, and adrenergic receptor b3 (ADRb3), were proportionally lower in cells treated with 50 mM TEL than in cells treated with 1 mM ROSI (Figure 1B)

Summary

Introduction

Peroxisome proliferator activated receptor gamma (PPARc) belongs to a family of DNA-binding nuclear receptors and functions as an adipocyte-specific transcription factor and a key regulator of cellular insulin sensitivity [1]. When activated with full agonists, e.g. anti-diabetic TZDs rosiglitazone (ROSI) and pioglitazone, PPARc suppresses osteoblasts and promotes adipocytes development, and enhances support for osteoclast development [2,4,5,6]. The deleterious effect of TZDs on bone includes suppression of new bone formation and accumulation of large quantities of fat at the bone healing site [8,9], suggesting a possibility of significant orthopaedic complications in fracture healing of diabetic patients on therapy with full PPARc agonists. PPARc proadipocytic activity includes directing adipocytes to acquire a phenotype regulating either energy storage through lipogenesis or energy dissipation through lipolysis. The third type of adipocytes has been identified and named ‘‘beige’’ or ‘‘brite’’ because, while being located within WAT depots and perhaps originating from the same progenitors as white adipocytes, they may acquire BAT function for energy dissipation in response to cold or pharmacologic stimuli [15,16]

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