Endocrine Fibroblast Growth Factors 15/19 and 21: from feast to famine

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Genes & development (Impact Factor: 10.8). 02/2012; 26(4):312-24. DOI: 10.1101/gad.184788.111
Source: PubMed


We review the physiology and pharmacology of two atypical fibroblast growth factors (FGFs)-FGF15/19 and FGF21-that can function as hormones. Both FGF15/19 and FGF21 act on multiple tissues to coordinate carbohydrate and lipid metabolism in response to nutritional status. Whereas FGF15/19 is secreted from the small intestine in response to feeding and has insulin-like actions, FGF21 is secreted from the liver in response to extended fasting and has glucagon-like effects. FGF21 also acts in an autocrine fashion in several tissues, including adipose. The pharmacological actions of FGF15/19 and FGF21 make them attractive drug candidates for treating metabolic disease.

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    • "New knowledge of how osteoclastogenesis and bone resorption are regulated will provide key insights into disease pathology as well as better treatment. FGF21 is a powerful regulator of glucose and lipid metabolism , thus a potential new drug for obesity and diabetes that is currently in clinical trials (Cantó and Auwerx, 2012; Potthoff et al., 2012). We have recently identified FGF21 as a physiologically and pharmacologically significant negative regulator of bone mass (Wei et al., 2012), suggesting that skeletal fragility may be an undesirable consequence of chronic FGF21 administration. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) promotes insulin sensitivity but causes bone loss. It elevates bone resorption by an undefined non-osteoclast-autonomous mechanism. We have detected a pro-osteoclastogenic activity in the hepatic secretome that is increased by FGF21 and largely attributed to insulin-like growth factor binding protein 1 (IGFBP1). Ex vivo osteoclast differentiation and in vivo bone resorption are both enhanced by recombinant IGFBP1 but suppressed by an IGFBP1-blocking antibody. Anti-IGFBP1 treatment attenuates ovariectomy-induced osteoporosis and abolishes FGF21-induced bone loss while maintaining its insulin-sensitizing metabolic benefit. Mechanistically, IGFBP1 functions via its RGD domain to bind to its receptor integrin β1 on osteoclast precursors, thereby potentiating RANKL-stimulated Erk-phosphorylation and NFATc1 activation. Consequently, osteoclastic integrin β1 deletion confers resistance to the resorption-enhancing effects of both IGFBP1 and FGF21. Therefore, the hepatokine IGFBP1 is a critical liver-bone hormonal relay that promotes osteoclastogenesis and bone resorption as well as an essential mediator of FGF21-induced bone loss.
    Cell metabolism 10/2015; DOI:10.1016/j.cmet.2015.09.010 · 17.57 Impact Factor
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    • "In addition to refeeding, circulating FGF21 levels are elevated by overfeeding and insulin resistance [23] (Fig. 2). During overfeeding, as the nutrient load reaches excess, FGF21 may act in a compensatory manner to mitigate decreasing insulin sensitivity and facilitate insulin-stimulated disposal of excess glucose to brown adipose tissue [27] (Fig. 3). "
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    ABSTRACT: The metabolic fibroblast growth factors (FGFs), FGF1, FGF15/19, and FGF21 differ from classic FGFs in that they modulate energy homeostasis in response to fluctuating nutrient availability. These unique mediators of metabolism regulate a number of physiological processes which contribute to their potent pharmacological properties. Administration of pharmacological doses of these FGFs cause weight loss, increased energy expenditure, and improved carbohydrate and lipid metabolism in obese animal models. However, many questions remain regarding the precise molecular and physiological mechanisms governing the effects of individual metabolic FGFs. Here we review the metabolic actions of FGF1, FGF15/19, and FGF21 while providing insights into their pharmacological effects by examining known biological functions.
    Seminars in Cell and Developmental Biology 10/2015; DOI:10.1016/j.semcdb.2015.09.021 · 6.27 Impact Factor
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    • "Fibroblast growth factor 19 (FGF-19) and its mouse ortholog, FGF-15, have been recently identified as endocrine factors which exert hormonelike metabolic effects through activation of FGF receptors [1] [2] [3] [4]. FGF-19 is a postprandial hormone which is mainly produced in the distal part of the small intestine in response to bile acid secretion after meals [5] [6]. FGF-19 is released into the portal circulation with a peak plasma concentration 2–3 h after meals [7] [8] to regulate bile acid and lipid metabolism through repressing liver cholesterol 7α-hydroxylase (CYP7A1) gene, which encodes the rate-limiting enzyme of bile acid synthesis [9] [10]. "
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    ABSTRACT: Background: We investigated factors associated with fibroblast growth factor 19 (FGF-19) increment after oral glucose loading (OGL) in human subjects. Methods: A total of 240 outpatients without known diabetes who were previously admitted for coronary angiography underwent an oral glucose tolerance test. FGF-19 increment (pg/ml) was calculated as FGF-19 2 h after OGL minus fasting FGF-19. Results: Overall, FGF-19 significantly increased after OGL (from 123 [78~201] to 141 [80~237], p=0.001). By age tertiles (≦54, 55~64, ≧65), FGF-19 significantly increased only in patients aged ≧65 (from 143 [98~209] to 189 [124~332], p<0.001). By glucose regulation status, FGF-19 significantly increased in patients with normal glucose tolerance (from 117 [78~211] to 153 [106~325], p=0.014) and in patients with prediabetes (from 117 [73~179] to 123 [70~204], p=0.043), but not in patients with diabetes (from 181 [102~243] to 178 [111~275], p=0.139). FGF-19 significantly increased in patients on statin treatment (from 120 [78~207] to 145 [86~264], p<0.001), but not in patients not on statin therapy (from 125 [86~196] to 128 [68~230] pg/ml, p=0.676). These findings remained significant after adjustment for confounders. Conclusions: FGF-19 increment after OGL was positively associated with age, and negatively associated with abnormal glucose regulation and statin treatment.
    Clinica chimica acta; international journal of clinical chemistry 09/2015; 450. DOI:10.1016/j.cca.2015.09.006 · 2.82 Impact Factor
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