The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

Zhang, Yuan; Xie, Yang; Berglund, Eric D.; Coate, Katie C.; He, Tianbiao; Katafuchi, Tetsuro; Xiao, Guanghua; Potthoff, Matthew J.; Wei, Wei; Wan, Yihong; Yu, Ruth T.; Evans, Ronald M.; Kliewer, Steven A.; Mangelsdorf, David J.

doi:10.7554/elife.00065

Cited by 349 publications

(286 citation statements)

References 39 publications

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“…Furthermore, POLG mice fed chow have dramatically increased (4.7-fold) levels of fibroblast growth factor 21 (FGF21), an endocrine hormone known to mediate an adaptive response to starvation ( Fig. 1G) (12). Interestingly, HFD appears to synergistically increase FGF21 levels in POLG mice to roughly ninefold higher in comparison with WT mice fed chow or HFD (Fig.…”

Section: Resultsmentioning

confidence: 97%

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall

Whyte

Suh

et al. 2015

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

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Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

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Section: Resultsmentioning

confidence: 97%

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall

Whyte

Suh

et al. 2015

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

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“…Similarly, in this study we observed an upregulation of renal FGF21 mRNA in MR-fed mice compared to controls which may contribute to the insulin-sensitizing effects observed in the kidneys of these animals. FGF21 is a hormone released by the liver in response to caloric restriction and markedly extends the lifespan of mice when overexpressed (31). The kidney has been identified as a target of FGF21, and exogenous administration of FGF21 protein has been shown to improve systemic metabolism and exert antifibrotic properties in kidneys of db/db mice (16).…”

Section: Discussionmentioning

confidence: 99%

Methionine restriction improves renal insulin signalling in aged kidneys

Grant

Lees

Forney

et al. 2016

Mechanisms of Ageing and Development

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Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190 days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression.

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“…Interestingly, recent studies have shown that the mammalian lifespan-promoting hormone FGF21 (ref. 29) also controls female reproduction 30 and that its expression is regulated by the nuclear hormone receptors farnesoid X receptor and liver X receptor, both of which are NHR homologues, and is induced by bile acids similar to D 7 -DA 31,32 . Our findings therefore establish the molecular basis for the interplay between nutrition and reproduction in regulating lifespan.…”

Section: Daf-7(e1372);nhr-8(ok186) Bdmentioning

confidence: 99%

Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans

et al. 2014

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Dietary restriction (DR) increases healthspan and longevity in many species, including primates, but it is often accompanied by impaired reproductive function. Whether signals associated with the reproductive system contribute to or are required for DR effects on lifespan has not been established. Here we show that expression of the cytochrome P450 DAF-9/CYP450 and production of the steroid hormone D 7 -dafachronic acid (DA) are increased in C. elegans subjected to DR. DA signalling through the non-canonical nuclear hormone receptor NHR-8/NHR and the nutrient-responsive kinase let-363/mTOR is essential for DR-mediated longevity. Steroid signalling also affects germline plasticity in response to nutrient deprivation and this is required to achieve lifespan extension. These data demonstrate that steroid signalling links germline physiology to lifespan when nutrients are limited, and establish a central role for let-363/mTOR in integrating signals derived from nutrients and steroid hormones.

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The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

Cited by 349 publications

References 39 publications

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Methionine restriction improves renal insulin signalling in aged kidneys

Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans

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