Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21

Abstract

Fibroblast growth factors (FGFs) 15/19 and 21 belong to a subfamily of FGFs that function as hormones. Produced in response to specific nutritional cues, they act on overlapping sets of cell surface receptors composed of classic FGF receptors in complex with βKlotho, and regulate metabolism and related processes during periods of fluctuating energy availability. Pharmacologically, both FGF15/19 and FGF21 cause weight loss and improve both insulin-sensitivity and lipid parameters in rodent and primate models of metabolic disease. Recently, FGF21 was shown to have similar effects in obese patients with type 2 diabetes. We discuss here emerging concepts in FGF15/19 and FGF21 tissue-specific actions and critically assess their putative role as candidate targets for treating metabolic disease.

Keywords: arginine vasopressin; brown adipose tissue; corticotropin-releasing factor; hypothalamus; sympathetic nervous system; βKlotho.

Figure 1. Schematic representation of the beneficial pharmacological actions of FGF19 and FGF21

In obese animals, pharmacologic administration of FGF19 and FGF21 causes weight loss and increases insulin sensitivity. FGF21 increases thermogenic energy expenditure through its coordinate action on adipose tissue and the hypothalamus to mobilize glucose and lipids, and to stimulate sympathetic nerve activity via AVP and CRF. These effects of FGF21 require signalling through βKlotho and one of the FGFRs (likely FGFR1c). In this way, FGF21 provides both the fuel (oxidative substrate) and the fire (beta adrenergic signaling) to drive heat production in the obese state. FGF19 works directly on liver through βKlotho and FGFR4 to decrease bile acid synthesis and provide beneficial effects on cholestatic diseases. In addition, FGF19 suppress hepatic glucose and lipid production, but may also improve metabolic parameters by activating similar processes to FGF21 in adipose and the CNS.