Fibroblast growth factor 21: from pharmacology to physiology^12,34

INTRODUCTION

Hormones such as insulin and glucagon have well-established roles in controlling substrate utilization and energy balance in response to nutritional status. In recent years, additional metabolic hormones, which include fibroblast growth factor 21 (FGF21), have been identified. FGF21 is a member of a family of atypical fibroblast growth factors (FGFs), which include FGF15/19 (FGF15 and FGF19 are mouse and human orthologs, respectively) and FGF23, which lack the conventional FGF heparin-binding domain (1, 2). As a consequence, these FGFs can diffuse away from their tissues of origin and function as hormones. FGF15/19 and FGF23 play prominent roles in regulating bile acid and phosphate homeostasis, respectively (3, 4).

FGF21 is abundantly expressed in liver, pancreas, and white adipose tissue (WAT) (5, 6). FGF21 signals through cell-surface receptors composed of the classic FGF receptors, which are tyrosine kinases, complexed with β-Klotho, a recently characterized single-pass membrane-spanning protein with 2 glycosidase domains (7–10). In vitro studies indicate that FGF21 prefers the FGFR1c/β-Klotho complex over those containing other FGFR isotypes (9, 10). Nevertheless, there is evidence that FGF21 can act through all 4 FGFR isotypes. Whereas the FGFRs are broadly expressed, β-Klotho is expressed in a more select set of tissues that include liver, WAT, pancreas, and testes (10, 11). It is anticipated that these will be important sites of FGF21 action.

FGF21 PHARMACOLOGY: EFFECTS ON METABOLISM

The role of FGF21 in regulating metabolism was first described by Kharitonenkov et al (12), who reported that FGF21 stimulated glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes. They further showed that FGF21 has remarkable in vivo effects. Transgenic mice overexpressing FGF21 in liver had improved insulin sensitivity and glucose clearance, reduced plasma triglyceride concentrations, and were resistant to weight gain when fed a high-fat diet (12). Administration of recombinant FGF21 to obese, insulin-resistant ob/ob or db/db mice or to Zucker diabetic fatty rats caused similar effects, which include reductions in plasma glucose and insulin concentrations. Subsequent studies by this group and others showed that administration of FGF21 to high-fat-diet–induced obese mice increased fat utilization and energy expenditure and reduced plasma glucose, insulin, and lipid concentrations and hepatic triglyceride concentrations (12–14). FGF21 also improved hepatic and peripheral insulin sensitivity in both high-fat-diet–induced obese and lean mice. In one study, it was shown that the decrease in hepatic triglyceride concentrations was accompanied by a decrease in lipogenic gene expression (14).

In similar studies performed with diabetic rhesus monkeys, FGF21 caused significant decreases in fasting plasma glucose, insulin, and triglycerides (15). FGF21 also lowered LDL cholesterol, increased HDL cholesterol, and caused modest weight loss. Importantly, FGF21 did not cause hypoglycemia either in this primate model or in any of the rodent models.

There is evidence that FGF21 exerts some of its effects directly on the endocrine pancreas. Short-term treatment of normal or db/db mice with FGF21 lowered plasma insulin concentrations (16). Immunostaining of pancreases from db/db mice showed increases in both the number of islets and the amount of insulin per islet in FGF21-treated animals. However, FGF21 did not affect islet cell proliferation (16). In in vitro studies, FGF21 increased insulin mRNA and protein amounts in islets isolated from healthy rats and protected them from glucolipotoxicity and cytokine-induced apoptosis (16). In addition to its effects on insulin, FGF21 suppressed glucagon secretion from isolated rat islets and reduced plasma glucagon concentrations in mice (12).

In summary, FGF21 has profound effects on carbohydrate and lipid metabolism in rodents and primates. Thus, FGF21 is a promising clinical candidate for the treatment of type 2 diabetes and perhaps other components of metabolic disease.

FGF21 PHYSIOLOGY: ROLES IN THE ADAPTIVE STARVATION RESPONSE

In 2007, 3 groups reported that FGF21 mRNA concentrations are markedly induced in murine liver by fasting through a mechanism requiring peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor activated by fatty acids and the fibrate class of triglyceride-lowering drugs (17–19). Consistent with this finding, FGF21 is also induced by fibrates and other synthetic PPARα agonists as well as by a ketogenic diet (17–19). FGF21 in turn has diverse effects in mice that include altering metabolism, sensitizing the mice to the hibernation-like state of torpor, and blunting the growth hormone (GH)–signaling pathway. Because all of these effects can be elicited by prolonged fasting, we conclude that FGF21 plays an overarching role in coordinating the adaptive starvation response. The effects of FGF21 on metabolism, torpor, and GH signaling are summarized below.

FGF21 IN WAT

Both β-Klotho and FGFR1c, which constitute the preferred FGF21 receptor complex, are highly expressed in WAT (10). Consistent with this finding, FGF21 stimulates glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes (12). FGF21 also induces the expression of hormone-sensitive lipase and adipocyte triacylglycerol lipase in WAT in mice (13, 18), which suggests that FGF21 plays a role in the mobilization of fatty acids from WAT to liver during fasting. However, although we observed that treatment of 3T3-L1 adipocytes with FGF21 stimulated glycerol release—a surrogate measure of lipolysis—another group observed that FGF21 suppressed lipolysis in 3T3-L1 adipocytes and human adipocytes (18, 30). The basis for these differences is not clear. Interestingly, FGF21 is induced by the thiazolidinedione antidiabetic drugs in WAT of db/db mice (6) and in 3T3-L1 adipocytes (31). The thiazolidinedione drugs, which include rosiglitazone (Avandia; GlaxoSmithKline, London, United Kingdom) and pioglitazone (Actos; Takeda Pharmaceutical Co Ltd, Osaka, Japan), increase insulin sensitivity by activating peroxisome proliferator-activated receptor γ (PPARγ), which is highly expressed in WAT. These findings raise the intriguing possibility that FGF21 contributes to the therapeutic actions of thiazolidinediones. The functions of FGF21 in WAT and whether they contribute to the pharmacologic actions of thiazolidinediones represent important areas for future investigation.

FGF21 IN HUMANS

Several recent studies have examined FGF21 in humans. Galman et al (21) showed that in a population of healthy subjects, serum FGF21 concentrations varied over a 250-fold range and did not relate to age, sex, body mass index, serum lipids or plasma glucose. In addition, they showed that circulating concentrations of FGF21 increase in humans only after a 7-d fast and that hypertriglyceridemic patients had 2-fold elevated FGF21 concentrations, which were further increased by treatment with the PPARα agonist fenofibrate. These data support the hypothesis that FGF21 is induced by prolonged fasting in humans as it is in mice, perhaps via a PPARα-dependent mechanism.

Several recent reports showed that circulating FGF21 concentrations were increased in subjects who were either overweight or had type 2 diabetes or impaired glucose tolerance (32–35). Conversely, circulating FGF21 concentrations were significantly reduced in subjects with anorexia nervosa (36). FGF21 concentrations correlated with body weight and/or adiposity (33, 35, 36). Similarly, circulating FGF21 concentrations were increased in db/db mice as were FGF21 mRNA concentrations in both liver and WAT (35).

These findings raise a series of interesting questions: Why is a hormone that is induced during fasting also increased under conditions of obesity and insulin resistance? Does this perhaps reflect FGF21 resistance or a compensatory response? How does a hormone that enhances gluconeogenesis during fasting in lean mice cause insulin sensitization and decreased hepatic glucose output in insulin-resistant animals? And what is the role of FGF21 expression in WAT? Does WAT release FGF21 into the circulation as does the liver? Regarding this last question, plasma FGF21 concentrations are increased in db/db mice treated with thiazolidinediones (6).

In summary, FGF21 has emerged as a powerful hormonal regulator of metabolism. From a physiologic perspective, FGF21 has provided important insights into how diverse aspects of the adaptive starvation response, ranging from hepatic metabolism to torpor, are elicited and coordinated. Pharmacologically, FGF21 is a promising new clinical candidate for the treatment of insulin resistance and other aspects of the metabolic syndrome. Despite the rapid progress that has been made in understanding FGF21's myriad actions, there is still much to be learned about the physiology and pharmacology of this fascinating hormone. (Other articles in this supplement to the Journal include references 37–40.)