Editors' ChoiceMetabolism

FGF21: How sweet it is!

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Science Translational Medicine  20 Jan 2016:
Vol. 8, Issue 322, pp. 322ec11
DOI: 10.1126/scitranslmed.aaf0862

Carbohydrates are an important source of energy for many animal species, but excessive consumption can cause obesity, liver toxicity, and metabolic syndrome. Fibroblast growth factor 21 (FGF21) is a pleotropic liver-derived hormone that regulates diverse aspects of energy homeostasis, circadian behavior, growth, and female reproduction. Now, Talukdar et al. show that FGF21 suppresses sweet and alcohol preferences in mice and sweet preference in monkeys by decreasing dopamine, a key neurotransmitter in reward pathways in the brain.

FGF21 levels increase in response to carbohydrate consumption in rodents and humans, and certain SNPs in the FGF21 gene are associated with increased carbohydrate consumption in humans. FGF21 is known to elicit its effects in the brain through a cell surface receptor that is composed of FGF receptor 1 and the β-Klotho receptor, a β-glucuronidase implicated in insulin sensitivity and aging. Transgenic Fgf21 mice that express supraphysiological levels of FGF21 or wild-type mice that received exogenous FGF21 showed significant decreases in both sucrose and saccharin preferences. These decreases were abrogated in mice that specifically lacked the β-Klotho receptor in the brain. Administration of FGF21 similarly decreased ethanol preference in mice but had no effect on responses to fatty acids and bitter taste. The effect of FGF21 on carbohydrate preference was also observed in nonhuman primates (obese cynomolgus monkeys). FGF21 receptor expression was localized specifically in the brain’s mesolimbic pathway [ventral tegmental area (VTA) and nucleus accumbens (NAc)], which regulates reward behavior primarily through dopamine signaling. Indeed, FGF21 administration decreased dopamine and its metabolites in the NAc.

Long-acting FGF21 analogues are currently in clinical trials for the treatment of obesity and type 2 diabetes. Although the mechanism by which FGF21 reduces dopamine concentrations remains unknown, these findings warrant additional studies to evaluate FGF21’s effects on carbohydrate preference and other reward behavior in humans.

S. Talkudar et al., FGF21 regulates sweet and alcohol preference. Cell Metab. 10.1016/j.cmet.2015.12.008 (2015). [Abstract]

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