Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF21 for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF21-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF21 to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF21 exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities.

OBJECTIVEFibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.RESEARCH DESIGN AND METHODSTo test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21.RESULTSWhen obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice.CONCLUSIONSThese data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.

FGF21 is a critical metabolic regulator, pivotal for fasting adaptation and directly regulated by PPARalpha in rodents. However, the physiological role of FGF21 in man is not yet defined and was investigated in our study. Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, gender, body mass index (BMI), serum lipids, or plasma glucose. FGF21 levels had no diurnal variation and were unrelated to bile acid or cholesterol synthesis. Ketosis induced by a 2 day fast or feeding a ketogenic diet (KD) did not influence FGF21 levels, whereas a 74% increase occurred after 7 days of fasting. Hypertriglyceridemic nondiabetic patients had 2-fold elevated FGF21 levels, which were further increased by 28% during fenofibrate treatment. FGF21 circulates in human plasma and increases by extreme fasting and PPARalpha activation. The wide interindividual variation and the induction of ketogenesis independent of FGF21 levels indicate that the physiological role of FGF21 in humans may differ from that in mice.

Fibroblast growth factor-21 (FGF21) functions as a metabolic regulator. The FGF21 transcript is reported to be abundantly expressed in liver, but little is known about the regulation of FGF21 expression in other tissues. In this study, we show that levels of FGF21 protein expression were similar in skeletal muscle and liver from fasted mice. FGF21 transcript and protein expression were upregulated in gastrocnemius muscle of skeletal muscle-specific Akt1 transgenic mice. Serum concentration of FGF21 was also increased by Akt1 transgene activation. In cultured skeletal muscle cells, FGF21 expression and secretion was regulated by insulin, Akt transduction and LY294002. These data indicate that skeletal muscle is a source of FGF21 and that its expression is regulated by a phosphatidylinosistol 3-kinase (PI3-kinase)/Akt1 signaling pathway-dependent mechanism.

Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that betaKlotho is an integral part of an activated FGF-21-betaKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking betaKlotho did not respond to FGF-21; the introduction of betaKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that betaKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, betaKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that betaKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects.