RESEARCH HIGHLIGHTS Nature Reviews Endocrinology 9, 563 (2013); published online 27 August 2013; doi:10.1038/nrendo.2013.168 NEUROENDOCRINOLOGY FGF21—central pathways of action unravelled wo new studies published in Nature β-klotho was selectively eliminated in the Medicine implicate the central SCN and DVC but not in other tissues), Tnervous system in the mechanisms to study the biological consequences of of action by which fibroblast growth chronic FGF21 exposure or of eliminating factor 21 (FGF21) exerts its effects central FGF21 action, respectively. on metabolism and growth in mice. To examine the effects of FGF21 on Furthermore, the data reveal hitherto circadian rhythm, Kliewer and colleagues unknown actions of centrally acting performed wheel-running experiments. FGF21: the induction of glucocorticoid “These experiments were the logical next levels, the inhibition of female ovulation, step once we found β-klotho in the SCN, and the alteration of circadian behaviour. the master regulator of circadian rhythm,” The hepatokine FGF21 has important explains Kliewer. roles in energy metabolism. For example, The studies showed that “many if FGF21 is well-known to induce metabolic not most of FGF21’s biological actions © iStockphoto/Thinkstock processes in response to starvation, such require it to act on the brain,” as Kliewer to long-term fasting, FGF21 is released as increased ketogenesis and inhibition describes it. Previously established from the liver and circulates to the brain, of growth. Direct effects of FGF21 on effects of FGF21—that is, the induction where it acts to regulate diverse aspects of peripheral target tissues, such as white of metabolic processes such as increased the adaptive starvation response in other adipose tissue, have previously been fatty acid oxidation, reduced insulin levels tissues,” comments Kliewer. “These effects reported. In addition, evidence of an and suppression of whole-body growth include increasing fatty acid oxidation and indirect mode of action of FGF21 via in response to starvation—required glucocorticoid concentrations, inhibiting the central nervous system has steadily expression of β-klotho in the brain. In growth and female reproduction, and increased; for example, administration addition to these effects, centrally acting changing circadian behaviour so as to of exogenous FGF21 directly into the FGF21 altered circadian behaviour optimize food-seeking behaviour.” ventricular system of obese rodent brains and increased systemic corticosterone Pharmacologically, FGF21 causes weight increased energy expenditure and insulin levels, a known characteristic of fasting loss and improves insulin sensitivity and sensitivity. However, the distinct site and starvation. “Importantly, both lipid parameters in rodent and monkey of central action and the mechanistic pharmacological and physiological models of obesity and insulin resistance. pathways linking to the periphery have concentrations of FGF21 acted on the Using the tissue-specific Klb knockout remained elusive. brain to modulate energy metabolism,” mice, Kliewer and co-workers are currently Researchers from the University of says Nobuyuki Itoh (Kyoto University testing whether these actions require Texas Southwestern Medical Center Graduate School of Pharmaceutical centrally acting FGF21 in obese mice. used laser-capture microdissection Sciences), who was not affiliated with “The pharmaceutical interest in coupled with quantitative PCR to map the studies. FGF21 for treating metabolic disease the mRNA for β-klotho—an essential Another physiology that is affected is tremendous, and several companies protein component of the FGF receptor— by starvation is reproduction; fertility have FGF21 in clinical trials,” states to two small regions of the brain: the is markedly reduced as a result. As Kliewer. “If the effects of FGF21 on suprachiasmatic nucleus (SCN) in reported in a second study, the teams led glucocorticoids and female fertility the hypothalamus and the dorsal–vagal by Kliewer and Mangelsdorf found that translate to humans, these factors are likely complex (DVC) in the hindbrain. “This mice chronically exposed to FGF21 (via to be major liabilities.” However, whether finding was very exciting, as these regions transgenic overexpression) were infertile these concerns are justified, remains to regulate not only female reproduction but and exhibited signs of hypothalamic be determined. also metabolism and, in the case of the hypogonadism. The effects of FGF21 on SCN, circadian rhythm,” recalls Steven A. glucocorticoids and female reproduction Linda Koch Kliewer, who led the studies together with were probably mediated by suppressing David J. Mangelsdorf. expression of the neuropeptide vasopressin Original articles Bookout, A. L. et al. FGF21 regulates Next, the investigators used genetically in the SCN. metabolism and circadian behavior by acting on the nervous engineered mouse models, such as Fgf21- Taken together, the findings suggest a system. Nat. Med. doi:10.1038/nm.3249 | Owen, B. M. overexpressing and conditional Klb unifying explanation for the actions of et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. doi:10.1038/nm.3250 knockout mice (in which the gene encoding FGF21 during starvation. “In response NATURE REVIEWS | ENDOCRINOLOGY VOLUME 9 | OCTOBER 2013 © 2013 Macmillan Publishers Limited. All rights reserved.