FGF21 Conducts a Metabolic Orchestra and Fat Is a Key Player

In recent years, much attention has been given to fibroblast growth factor (FGF)21 and its role as a metabolic regulator, both of specific organs and the mammalian organism as a whole. Interest was sparked in 2005, when Kharitonenkov et al (1) discovered that FGF21 had profound positive effects on glucose uptake, lipid clearance, and insulin levels and that elevating FGF21 protein levels was protective against dietinduced obesity in mice. Since this discovery, human studies haveconsistently shownthat circulating levelsofFGF21correlate with obesity and the metabolic syndrome (2, 3), whereas murine studies confirm this phenotypic relationship and support the premise that obesity represents an FGF21resistant state (4, 5). These findings have fueled excitement for the possibility of exploiting FGF21 or its signaling pathways therapeutically in target tissues. Indeed, early trials using FGF21 analogs have already shown promising results, with2compounds todatebeingeffectiveat improvingserum lipid profiles and markers of cardiovascular disease risk, while reducing body weight in obese diabetic patients (6, 7). FGF21 regulates these distinct yet closely related components of metabolism through its ability to influence key metabolic pathways in multiple tissues, in a coordinated fashion. Although most FGF proteins work by exerting autocrine/paracrine effects on cell growth, division and mitosis, the structure of the “atypical” FGF proteins (FGF19, FGF21, and FGF23) enables their secretion, circulation and endocrine actions (8). The liver is the primary site of FGF21 production, with expression also detected in muscle and brown adipose tissue (BAT) under certain conditions (9–12). Although FGF receptors (FGFR) are expressed in a wide range of tissues, its sites of action are inferred by the more restricted expression profile of FGF21’s essential coreceptor, -Klotho (13). -Klotho is expressed at the highest levels in liver and adipose tissues, followed by pancreas and the colon, where it complexes with FGFR1–FGFR4 to form receptors for FGF21 (14). The physiological role of FGF21 in these tissues has been detailed extensively in a previous review of the subject (15), but in summary, it regulates the adaptive response to fasting via its induction in states that require increased fatty acid oxidation. Interestingly, however, FGF21 also enhances glucose uptake in the fed state via up-regulation of the insulin-independent glucose transporter 1 and increases lipid handling and oxidation pathways in liver and adipose tissues via peroxisome proliferator-activated receptorcoactivator 1 (16–18). As such, it has been suggested that just as insulin and glucagon coordinate acute responses to changes in nutrient availability, FG21 and its relative FGF19 (FGF15 in mice) regulate longer term adaptive changes to energy scarcity or excess (15). It is somewhat of an understatement to say that, after almost a century of research, the complexities of insulin signaling are still not fully understood. Therefore it is highly likely that thephysiologyandregulationofFGF21signaling, as an adaptive regulator of metabolism and fuel substrate utilization in multiple tissues, is equally complex and caveatridden. Much of what is known comes from studies of mice that completely lack FGF21, or those that have increased circulating amounts of the protein. These models show clearly that FGF21 plays an important role in glucose homeostasis, energy balance, BAT thermogenesis and lipid clearance, particularly during fasted and overfed states (1, 17, 19). Treatment studies have identified powerful roles for FGF21 in BAT, where it acts as the activation signal for ther-