FGF21 regulates metabolism and circadian behavior by acting on the nervous system

Bookout, Angie L.; Groot, Marleen H. M. de; Owen, Bryn M.; Lee, Syann; Gautron, Laurent; Lawrence, Heather L; Ding, Xunshan; Elmquist, Joel K.; Takahashi, Joseph S.; Mangelsdorf, David J.; Kliewer, Steven A.

doi:10.1038/nm.3249

Cited by 442 publications

(496 citation statements)

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“…S2F), which was recently found to increase the hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH secretion and, subsequently, corticosterone production (24). Thus, the RF-dependent increase in the FGF21 level provides a rationale for the previously reported suprachiasmatic nucleus (SCN)-independent corticosterone production during RF (21).…”

Section: An Increased Glucagon Secretion Results In An Activation Of mentioning

confidence: 91%

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Mukherji

Kobiita

Chambon

2015

Proc. Natl. Acad. Sci. U.S.A.

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The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα-RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs.shifted eating | shifted peripheral circadian clocks | metabolic alterations | RevErbα | PPARα P ioneering studies (1, 2) have established that switching the feeding time in mice from the "active" phase [dark period of the light-dark (L/D) cycle] to the "rest" phase (light period), i.e., restricted feeding (RF), overrides the suprachiasmatic nucleus (SCN) circadian clock (CC)-derived signals and acts as a "zeitgeber" for peripheral CCs (PCCs), leading to a 12-h shift in the time at which components of PCCs are expressed. Numerous studies have shown that under homeostatic conditions, the functions of PCCs and metabolism are tightly linked and that perturbations in their interactions leads to pathologies, e.g., obesity and metabolic syndrome (3-5).The identity of some of the molecular pathways that couple PCCs to metabolism are known (3-5), but it is largely unknown how environmental cues, e.g., altered feeding schedules, may directly perturb the expression of individual CC components (5-7), thereby leading to obesity and a metabolic syndrome-like pathology (5). Assuming that specific metabolic perturbations generated by switching the feeding time could selectively affect the time of expression of some of the CC core components, we looked for both metabolic and PCC alterations at early RF times. We report here a comprehensive temporal analysis, an...

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Section: An Increased Glucagon Secretion Results In An Activation Of mentioning

confidence: 91%

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Mukherji

Kobiita

Chambon

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Continuous intracerebroventricular injection of FGF21 into obese rats increases energy expenditure and insulin sensitivity (12). More recently, FGF21 has been shown to act on the central nervous system to increase systemic glucocorticoid levels, suppress physical activity, and alter circadian behavior (13). Furthermore, FGF21 acts on the hypothalamus to suppress the vasopressinkisspeptin signaling cascade, thereby mediating starvationinduced infertility of female mice (14).…”

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confidence: 99%

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

et al. 2014

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Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocytesecreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor a (PPARa) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARa KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARa KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signalrelated kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.Hepatic gluconeogenesis is tightly controlled by counterregulatory hormones such as glucagon, cortisol, and insulin, via regulating the expression of key gluconeogenic enzymes, including glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Fibroblast growth factor 21 (FGF21), a metabolic regulator mainly secreted from the liver in response to fasting and starvation under the control of the nuclear receptor peroxisome proliferatoractivated receptor a (PPARa), plays a critical role in maintaining energy homeostasis and insulin sensitivity in both rodents and nonhuman primates (1-6). A therapeutic dose of FGF21 decreased blood glucose in diabetic animals without causing hypoglycemia (4). FGF21 has also been shown to act as a key downstream effector of PPARa, mediating several metabolic adaptation responses to starvation, including hepatic fatty acid oxidation, ketogenesis, and growth hormone resistance (1,2,7). In addition, FGF21 is implicated in hepatic gluconeogenesis, although it remains controversial whether hepatocytes are a direct action site of FGF21 (8,9). There is an obvious dichotomy between the effects of endogenous FGF21 and pharmacological actions of the recombinant peptide with respect to hepatic metabolism (4,6,9).FGF21 can cross the blood-brain barrier (10) and is detectable in both human and rodent cerebrospinal fluid (10,11). Continuous intracerebroventricular injection of FGF21 into obese rats increases energy e...

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“…Some of the associations are consistent with those observed in studies of mice that suggest FGF21 is a "global starvation" signal. For example, the allele that increases sugar intake, is associated with lower levels of physical activity and altered chronotype, both features of mice with higher FGF21 [25], but not with female reproductive traits or bone mineral density.…”

Section: Discussionmentioning

confidence: 99%

“…FGF21 has multiple metabolic effects, possibly all linked to a role as a "global starvation signal" [25], and studies in mice have identified links to growth, bone metabolism [21], circadian rhythms [25], physical activity [25] and reproductive traits [26]. We therefore performed a "Phenome wide association study" (PheWAS), testing the association of the FGF21 rs838133 variant with 105 traits in UK Biobank in the 451,000 individuals of European ancestry.…”

Section: Phenome Wide Association Study Shows Suggestive Associationsmentioning

confidence: 99%

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

et al. 2017

Preprint

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word summaryFibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21's therapeutic potential. IntroductionFGF21 is a hormone secreted primarily by the liver whose multiple functions include signalling to the paraventricular nucleus of the hypothalamus to suppress sugar and alcohol intake [1,2], stimulating insulin-independent glucose uptake by adipocytes [3] and acting as an insulin sensitizer [4]. These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6]. An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7]. A recent study suggested that FGF21 analogues may alter not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/214700 doi: bioRxiv preprint first posted online Nov. 6, 2017; blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3]. Subsequent studies have confirmed these findings in mice [10] and shown similar effects in non human primates, including improvement of glucose tolerance and slight weight loss in diabetic rhesus monkeys [11], but other studies are less conclusive [5].Recent studies have shown that FGF21 affects the balance of macronutrients consumed. Studies in mice and non human primates show that genetically and pharmacologically raising FGF21 levels suppresses sugar and alcohol intake [1,2]. Three human genetic studies have shown that the minor A allele at rs838133 (A/G, Minor Allele Frequency=44.7%), which results in a synonymous change to the first exon of FGF21, is associated with higher carbohydrate and lower...

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FGF21 regulates metabolism and circadian behavior by acting on the nervous system

Cited by 442 publications

References 36 publications

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

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