Article

Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ.

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2012; 109(8):3143-8. DOI: 10.1073/pnas.1200797109
Source: PubMed

ABSTRACT The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.

Download full-text

Full-text

Available from: Yihong Wan, Jul 03, 2015
0 Followers
 · 
252 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states.
    Cell Metabolism 07/2014; 20(2). DOI:10.1016/j.cmet.2014.06.003 · 16.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here, we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R null mice exhibit low bone mass owing to elevated circulating leptin, whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R null mice exhibit high bone mass owing to a differentiation shift from marrow adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant because bone mass is reduced in orexin null and OX1R2R double null mice but enhanced in orexin-overexpressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation and highlight orexin as a therapeutic target for osteoporosis.
    Cell metabolism 04/2014; DOI:10.1016/j.cmet.2014.03.016 · 16.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone marrow mesenchymal stem cells (BMMSCs) are multipotent marrow stromal cells with the ability to differentiate into a variety of cell types required for tissue regeneration including osteoblasts and chondrocytes. Thus, they hold tremendous potential as powerful therapeutic strategies for the prevention and treatment of degenerative disorders including osteoporosis and osteoarthritis. The differentiation of BMMSCs into competing lineages such as osteoblasts and marrow adipocytes is regulated by various environmental cues and intrinsic signaling pathways. Here I highlight recent advances in the understanding of BMMSC function and regulation, including the interaction between BMMSCs with the hematopoietic/immune system, and the identification of novel modulators of BMMSC differentiation such as the metabolic hormone fibroblast growth factor 21 (FGF21). These new findings will further elucidate the dynamic regulation of BMMSCs in the pathophysiological control of skeletal homeostasis, and facilitate the clinical applications of BMMSCs in regenerative medicine.
    The international journal of biochemistry & cell biology 12/2012; 45(3). DOI:10.1016/j.biocel.2012.12.014 · 4.24 Impact Factor