Energy Balance, Myostatin, and GILZ: Factors Regulating Adipocyte Differentiation in Belly and Bone

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) belongs to the nuclear hormone receptor subfamily of transcription factors. PPARs are expressed in key target tissues such as liver, fat, and muscle and thus they play a major role in the regulation of energy balance. Because of PPAR-gamma's role in energy balance, signals originating from the gut (e.g., GIP), fat (e.g., leptin), muscle (e.g., myostatin), or bone (e.g., GILZ) can in turn modulate PPAR expression and/or function. Of the two PPAR-gamma isoforms, PPAR-gamma2 is the key regulator of adipogenesis and also plays a role in bone development. Activation of this receptor favors adipocyte differentiation of mesenchymal stem cells, while inhibition of PPAR-gamma2 expression shifts the commitment towards the osteoblastogenic pathway. Clinically, activation of this receptor by antidiabetic agents of the thiazolidinedione class results in lower bone mass and increased fracture rates. We propose that inhibition of PPAR-gamma2 expression in mesenchymal stem cells by use of some of the hormones/factors mentioned above may be a useful therapeutic strategy to favor bone formation.

Figure 1

Nutrition and tissue-generated hormonal signals modulate mesenchymal stem cell differentiation. Hormonal signals generated upon nutrient ingestion impact the organism's energy balance, thus favoring anabolic versus catabolic activities. In turn, hormonal signals generated by target tissues such as muscle, bone, and fat modulate MSC differentiation into adipocytes or osteoblasts.

Figure 2

PPAR-γ2 action is modulated by either changes in receptor expression or transcriptional activity. (a) Natural (insulin, long-chain fatty acids, or eicosanoids) or synthetic ligands (TZDs) to the PPAR-γ2 receptor can either increase or decrease receptor expression resulting in increased adipocytic or increased osteoblastic differentiation, respectively. (b) It is also possible to stimulate or inhibit PPAR-γ2 transcriptional activity resulting in either increased adipocytic or osteoblastic differentiation, respectively.