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

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2012; 109(8):3143-8. DOI: 10.1073/pnas.1200797109
Source: PubMed


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.

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    • "In nutrient-deficient conditions, FGF21-knockout mice exhibit less inhibition of skeletal growth than do control mice [32], which indicates that FGF21 has a causal role in the undernutrition-related reduction in bone growth. FGF21-induced bone loss is probably due to the direct suppression of osteoblastogenesis and chondrogenesis [32,37,38]. Thus, these results demonstrate the functional significance of FGF21 as a key regulator of skeletal homeostasis as well as liver and adipose tissue homeostasis in nutritionally stressful states. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is primarily expressed in the liver and exerts beneficial effects on obesity and related metabolic diseases. In addition to its remarkable pharmacologic actions, the physiological roles of FGF21 include the maintenance of energy homeostasis in the body in conditions of metabolic or environmental stress. The expression of FGF21 is induced in multiple organs in response to diverse physiological or pathological stressors, such as starvation, nutrient excess, autophagy deficiency, mitochondrial stress, exercise, and cold exposure. Thus, the FGF21 induction caused by stress plays an important role in adaptive response to these stimuli. Here, we highlight our current understanding of the functional importance of the induction of FGF21 by diverse stressors as a feedback mechanism that prevents excessive stress.
    Diabetes & metabolism journal 08/2014; 38(4):245-51. DOI:10.4093/dmj.2014.38.4.245
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    • "Given that low circulating adiponectin is associated with increased cancer risk and that adiponectin can limit tumor growth (Dalamaga et al., 2012), the consequences of elevated adiponectin during cancer therapy clearly warrant further investigation. Beyond cancer, many other conditions are associated with increases in both MAT and circulating adiponectin, including aging, estrogen deficiency , type 1 diabetes, and treatment with pharmacologic agents such as thiazolidinediones or fibroblast growth factor 21 (Combs et al., 2003; Fazeli et al., 2013; Isobe et al., 2005; Kharitonenkov et al., 2007; Scheller and Rosen, 2014; Wei et al., 2012; Ye and Scherer, 2013). This suggests that MAT might impact upon circulating adiponectin in other clinically relevant conditions. "
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    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 · 17.57 Impact Factor
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    • "Wei et al. utilized both genetic and pharmacologic FGF21 gain of function paradigms to demonstrate a striking decrease in bone mass in mice. Furthermore, FGF21KO mice exhibited a phenotype of increased bone mass [95] all together leading to the hypothesis that FGF21 is a critical regulator of bone turnover. Nevertheless, and given that FGF21Tg mice present with extended lifespan during which they remain apparently healthy [21], the question remains if this observed reduction in bone mass has any negative consequences. "
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    ABSTRACT: Since the discovery of insulin in 1921, protein therapeutics have become vital tools in the treatment of diabetes mellitus. This heritage has been extended with the comparatively recent introduction of recombinant and re-engineered insulins, in addition to the advent of GLP1 agonists. FGF21 represents an example of a novel experimental protein therapy which is able to induce favorable metabolic effects in various species ranging from rodents to man. The aim of this review is to communicate the story of the FGF21 drug discovery path from identification in a functional in vitro screen, to the eventual evaluation of its utility in patients. Given that the development of FGF21 advanced hand-in-hand with rapidly evolving scientific research around this target, we have also attempted to describe our view of recent developments regarding the mechanistic understanding of FGF21 biology.
    Molecular Metabolism 06/2014; 3(3):221-229. DOI:10.1016/j.molmet.2013.12.003
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