The many facets of PPARgamma: novel insights for the skeleton

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that functions as a master transcriptional regulator of adipocyte conversion. During PPARgamma transactivation, multiple signaling pathways interact with one another, leading to the differentiation of both white and brown adipose tissue. Ligand activation of the PPARgamma-RXR heterodimer complex also enhances insulin sensitivity, and this property has been heavily exploited to develop effective pharmacotherapies for the treatment of type 2 diabetes mellitus. PPARgamma is also expressed in stem cells and plays a critical role in mesenchymal stromal cell differentiation and lineage determination events. The many facets of PPARgamma activity within the bone marrow niche where adipocytes, osteoblasts, and hematopoietic cells reside make this molecule an attractive target for pharmacological investigation. Additional findings that osteoblasts can alter energy metabolism by influencing adiposity and insulin sensitivity, and observations of decreased bone turnover in diabetic subjects, underscore the contribution of the skeleton to systemic energy requirements. Studies into the role of PPARgamma in skeletal acquisition and maintenance may lead to a better understanding of the molecular mechanisms governing stromal cell differentiation in the mesenchyme compartment and whether PPARgamma activity can be manipulated to benefit skeletal remodeling events and energy metabolism.

Fig. 1.

The many facets of peroxisome proliferator-activated receptor (PPAR)γ, a nuclear receptor and transcription factor. PPARγ expression and activity is dependent on heterodimerization with RXRs, binding of endogenous or exogenous ligands, other transcription factors, posttranslational modifications such as phosphorylation or ubiquitination, and cell-autonomous circadian rhythms. PPARγ has three main functions: adipocyte differentiation, insulin sensitivity, and lineage allocation of mesenchymal stem cell (MSCs). All three are important for the skeleton and are ligand dependent.

Fig. 2.

PPARγ regulates MSC allocation. Determination of lineage allocation of MSCs is regulated by several transcription factors including PPARγ and CCAAT/enhancer binding proteins (C/EBPs), which govern adipogenesis, Runx2 (runt-related transcription factor), and Osx (osterix), which are necessary for osteoblastogenesis. PPARγ favors adipogenesis and suppresses osteoblastogenesis partly through inhibiting Runx2 function, resulting in the reduction of osteoblast pool in bone marrow.