REV-ERBα regulates <i>Fgf21</i> expression in the liver via hepatic nuclear factor 6

Chavan, Rohit; Preitner, Nadia; Okabe, Takashi; Strittmatter, Laureen Mansencal; Xu, Chao; Ripperger, Jürgen A.; Pitteloud, Nelly; Albrecht, Urs

doi:10.1242/bio.021519

Cited by 17 publications

(12 citation statements)

References 31 publications

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“…A study reported that Fgf21 expression is circadian in the liver, peaking during the fasting phase and under direct control of the circadian machinery 138 . However, transactivation of Fgf21 by BMAL1/CLOCK was not confirmed by an independent study 139 and serum levels of FGF21 are relatively stable under normal feeding regimens 137 , displaying a 24-h oscillatory pattern only following prolonged fasting 140, 141 . Nevertheless, FGF21 is able to modulate directly the central clock by activating β-Klotho signaling in the SCN.…”

Section: Metabolic Coupling Of Central and Peripheral Clocksmentioning

confidence: 91%

Circadian blueprint of metabolic pathways in the brain

Greco

Sassone–Corsi

2018

Nat Rev Neurosci

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The circadian clock is an endogenous, time-tracking system that directs multiple metabolic and physiological functions required for homeostasis. The master or “central” clock located within the suprachiasmatic nucleus (SCN) in the hypothalamus governs peripheral clocks present in all systemic tissues, contributing to their alignment and ultimately to temporal coordination of physiology. Accumulating evidence reveals the presence of additional clocks in the brain and suggests the possibility that circadian circuits may feedback to these from the periphery. Here, we highlight recent advances on the communications between clocks and discuss how they relate to circadian physiology and metabolism.

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Section: Metabolic Coupling Of Central and Peripheral Clocksmentioning

confidence: 91%

Circadian blueprint of metabolic pathways in the brain

Greco

Sassone–Corsi

2018

Nat Rev Neurosci

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“…It is also known that FGF21 has signaling connections to some important regulators of circadian metabolism, e.g. AMPK [127] and REV-ERBα [128]. Adiponectin, a target gene of FGF21 signaling, is under the circadian regulation [129].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity

Salminen

Kaarniranta

Kauppinen

2017

Cellular Signalling

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FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways. FGF21 is an interorgan regulator which can alleviate many age-related metabolic and stress disorders, e.g. through the activation of AMPK signaling. FGF21 signaling is also involved in circadian and torpor regulation. Given that circulating FGF21 can attenuate organelle stress, e.g. mitochondrial and ER stresses, it resembles a stress-induced cell non-autonomous regulation of proteostasis and longevity present in model organisms. The overexpression of FGF21 can even extend the lifespan of mice, probably by improving the healthspan. We will clarify the positive and negative signaling mechanisms which control the stress-related expression of FGF21 through the ISR pathway. Moreover, we will examine the role of FGF21 as an interorgan coordinator of survival functions in metabolic and stress disorders. We conclude that FGF21 can be viewed as a cell non-autonomous enhancer of longevity in mammals.

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“…FGF21 exhibits a diurnal rhythm in ( 52 , 53 ) and humans ( 54 ), and overexpression of FGF21 disrupts circadian locomotor behavior via hypothalamic Klb ( 33 ). Bookout et al ( 33 ) showed that overexpression of FGF21 reduces total running wheel behavior, with an increase in light phase activity, both of which are normalized in mice deficient for central Klb .…”

Section: Discussionmentioning

confidence: 99%

Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Nason¹,

Antipenko²,

Presedo³

et al. 2021

JCI Insight

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Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon’s weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.

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REV-ERBα regulates Fgf21 expression in the liver via hepatic nuclear factor 6

Cited by 17 publications

References 31 publications

Circadian blueprint of metabolic pathways in the brain

Circadian blueprint of metabolic pathways in the brain

Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity

Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

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