Fibroblast Growth Factor 21—Metabolic Role in Mice and Men

Abstract

Since its identification in 2000, the interest of scientists in the hepatokine fibroblast growth factor (FGF) 21 has tremendously grown, and still remains high, due to a wealth of very robust data documenting this factor's favorable effects on glucose and lipid metabolism in mice.For more than ten years now, intense in vivo and ex vivo experimentation addressed the physiological functions of FGF21 in humans as well as its pathophysiological role and pharmacological effects in human metabolic disease.This work produced a comprehensive collection of data revealing overlaps in FGF21 expression and function but also significant differences between mice and humans that have to be considered before translation from bench to bedside can be successful.This review summarizes what is known about FGF21 in mice and humans with a special focus on this factor's role in glucose and lipid metabolism and in metabolic diseases, such as obesity and type 2 diabetes mellitus.We highlight the discrepancies between mice and humans and try to decipher their underlying reasons.(Endocrine Reviews 38: 468 -488, 2017) W ith a prevalence of ~% in adults, type  diabetes mellitus (TD) is the most prominent metabolic disease worldwide (World Health Organization fact sheet on diabetes at http://www.who. int/mediacentre/factsheets/fs/en).The hallmark of the disease, that is, hyperglycemia, results from insulin resistance of liver, skeletal muscle, adipose tissue, and brain and a concomitant failure of pancreatic b-cells to compensate for this resistance by increased insulin secretion ().Current therapeutic options aim at reducing insulin resistance (metformin, thiazolidinediones), enhancing insulin secretion (sulfonylureas, meglitinides, dipeptidyl peptidase IV inhibitors, incretin mimetics), or excreting glucose via the urine (sodium/glucose cotransporter  inhibitors), but a progressive loss of b-cell function and mass is often observed ().Eventually, the ultima ratio to normalize blood glucose is the replacement of endogenous insulin by injection of human recombinant insulin or insulin analogs.New insights into the molecular pathomechanisms behind insulin resistance and b-cell failure point toward a crucial role for a well-balanced humoral crosstalk between metabolically relevant tissues (e.g., adipose, muscle, liver).Highly relevant players and promising targets for novel therapeutic strategies in this crosstalk were recently identified, among them fibroblast growth factor (FGF) (-).FGF is an endocrine factor secreted by liver acting as a metabolic regulator.Interest in the metabolic effects of FGF was aroused by the emergence of FGF as hit in an in vitro assay testing secreted proteins of unknown function for stimulation of glucose uptake in murine T-L adipocytes in an insulin-independent manner ().Based mainly on preclinical studies in mice showing improvements in glucose and lipid metabolism, FGF emerged as an interesting new candidate for TD treatment,