The Liver-Derived Endocrine Hormone FGF21 Alters Metabolism and Diurnal Behavior via the Nervous System




Bookout, Angie Lynn

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Fuel acquisition is essential to survival. During privation, the body protects glucose concentrations acutely by glycogenolysis, and later by gluconeogenesis and ketogenesis. Additionally, animals alter daily behavioral patterns to seek food, but eventually reduce energetically costly activities (growth, reproduction, locomotion). Little is known about the mechanisms that orchestrate and coordinate these physiological and behavioral responses to starvation. The liver-derived endocrine hormone fibroblast growth factor 21 (FGF21) is induced in chronic fasting and acts as a global starvation signal. Previous studies focusing on FGF21 as an anti-diabetic drug indicate that FGF21 coordinates whole-body fat utilization and energy expenditure. However, its basic physiological role is underexplored. Acute injection of recombinant FGF21 quickly elicits a coordinated program between tissues resulting in reduced plasma insulin and gluconeogenic and thermogenic gene expression programs in liver and brown adipose, effects that require an intact animal. Mice with chronic FGF21 overexpression (FGF21tg) are smaller in size, females are infertile, and if fasted, they undergo torpor, an energy-conserving process. Taken together, these data suggest that FGF21 may exert some effects through the nervous system. To explore this idea, I utilized anatomically-guided laser capture microdissection followed by quantitative, real-time PCR to profile expression of the FGF receptor/co-receptor family in specific hypothalamic nuclei of mice. Surprisingly, the FGFR1-IIIc/βKlotho complex is found in the suprachiasmatic nucleus (SCN), area postrema (AP), nucleus tractus solitarii (NTS), and nodose ganglion (cell body of vagus nerve), implicating roles in circadian and metabolic regulation. Results of surgical, pharmacological, and genetic strategies indicate the vagus senses circulating FGF21, resulting in adrenergic efferent responses that reduce insulin secretion, while a different adrenergic site modulates liver and brown adipose gene expression. Analyses of the effects of FGF21 on the SCN, the body’s master clock, using running wheels show FGF21tg mice have dramatically altered circadian activity, likely as a consequence of inhibiting SCN output functions. Deletion of βKlotho specifically from the SCN rescues this behavior in addition to growth defects of FGF21tg mice. To date, this is the first description of a liver-derived endocrine hormone that affects such diverse aspects of the starvation response by acting on the nervous system.

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