Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice

Abstract

Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions. We administered FGF21 into the central nervous system via lateral ventricle infusion into male mice and found that the central treatment increased norepinephrine turnover in target tissues that include the inguinal white adipose tissue and brown adipose tissue. Central FGF21 stimulated browning as assessed by histology, expression of uncoupling protein 1, and the induction of gene expression associated with browning. These effects were markedly attenuated when mice were treated with a β-blocker. Additionally, neither centrally nor peripherally administered FGF21 initiated browning in mice lacking β-adrenoceptors, demonstrating that an intact adrenergic system is necessary for FGF21 action. These data indicate that FGF21 can signal in the brain to activate the sympathetic nervous system and induce adipose tissue thermogenesis.

FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

“…administered FGF21 also exhibited significantly increased c-Fos staining in the PVN of the hypothalamus (Fig. 4E,F), consistent with a recent report observing increased ERK phosphorylation in the PVN in response to FGF21 administration (Douris et al, 2015). Finally, to examine the physiological significance of FGF21 signaling to the PVN on carbohydrate intake, we assessed HSD preference in a different cohort of PVN KLB KO mice and WT controls.…”

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

“…In mice, FGF21 increases corticotropin-releasing hormone expression in hypothalamus, circulating glucocorticoid concentrations, and sympathetic outflow (18)(19)(20), which are linked to heightened anxiety. We, therefore, tested Klb fl/fl and Klb Camk2a mice in behavioral paradigms measuring anxiety, including novelty suppressed feeding (Fig.…”

Modulation of energy balance by fibroblast growth factor 21

“…Then, this "new" BAT becomes the target of FGF21 and also a site of FGF21 synthesis and secretion [18,100]. Further mechanisms proposed are through hypothalamic adrenergic activation by FGF21 to induce BAT thermogenesis activating adenosine monophosphate (AMP) kinase (AMPK) and Sirt-1 (sirtuin protein 1) pathways [58,[120][121][122][123]. Patients with pheochromocytoma and very high adrenergic action occasioned by high catecholamine release by tumor showed higher proportion of beige cells in omental WAT with higher expression of FGF21 and UCP1 [23].…”