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Forever (FGF) 21

Nature Medicine volume 19, pages 1090–1092 (2013)Cite this article

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The fibroblast growth factor 21 (FGF21)–β-Klotho pathway orchestrates a switch to oxidative metabolism during fasting and starvation and has been implicated as a signal connecting nutrition, growth, reproduction and longevity. Two new studies in mice show that Fgf21 interacts directly with the brain circadian clock to coordinate activity and reproduction as part of the adaptation to fasting (pages 1147–1156).

Perhaps the best parody of our preoccupation with time is the beginning of Alice's Adventures in Wonderland, when Alice's ambassador to Wonderland, the White Rabbit, exclaims upon looking at his pocket watch, “Oh Dear! Oh Dear! I shall be late.” Although in her dream time seems mutable, upon awakening, Alice is confined by the steady cycle of day and night. Indeed, all forms of life on the surface of the Earth have an innate ability to track time that is programmed by an internal clock to anticipate the solar cycle (this cycle is termed circadian for circa diem, about a day). The circadian clock is encoded by a transcription-translation feedback loop composed of a pair of activators that induce the expression of their own repressors with a periodicity of approximately 24 hours. In animals, the molecular clock is present not only in pacemaker neurons of the brain, where it governs the sleep–wake and fasting–feeding cycles, but also in nearly every peripheral cell in the body, where it exerts broad effects on physiology. The communication between metabolic and circadian systems is bidirectional, and there is intensive investigation to identify the physiological signals that co-regulate these processes.

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Figure 1: The circadian clock in adaption to fasting mediated by FGF21.

Debbie Maizels

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  1. Joseph Bass is in the Division of Endocrinology, and the Department of Neurobiology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Chicago, Illinois, USA, Northwestern University, Evanston, Illinois, USA.,

    Joseph Bass

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  1. Joseph Bass
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Correspondence to Joseph Bass.

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Competing interests

J.B. is a consultant for and is on the Speakers' Bureau at Merck. He owns stock in and is on the scientific advisory board at Reset Therapeutics. He is a consultant for Gerson Lehrman Group. He is also on the scientific advisory boards of Janssen Pharmaceuticals and Vanda Pharmaceuticals.

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Bass, J. Forever (FGF) 21. Nat Med 19, 1090–1092 (2013). https://doi.org/10.1038/nm.3334

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