The role of FGF21 in aging and aging-related diseases
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE39313 | GEO | 2012/10/18
SECONDARY ACCESSION(S): PRJNA170543
REPOSITORIES: GEO
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Project description:Aging and aging-related diseases represent an increasing burden on modern society. Thus, drugs that retard the aging process are highly desirable. Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity and blocks somatic growth. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting AMP kinase or mTOR signaling or NAD metabolism. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used as a hormone therapy to extend lifespan. Liver, epididymal fat and gastrocnemius muscle RNA expression profiles were compared between C57Bl/6J ad libitum, fasted, and calorically restricted mice, as well as between FGF-21 transgenic and their wild-type C57Bl/6J controls.
2012-10-18 | E-GEOD-39313 | biostudies-arrayexpress
Project description:Progressive mitochondrial respiratory chain (RC) deficiency is associated with a wide spectrum of adult-onset degenerative diseases, as well as with normal aging. We have previously generated the Deletor mice to model late-onset progressive RC defects. Here we report novel tissue-specific pathways contributing to mitochondrial disease pathogenesis, identified by gene expression analysis. We found that RC-deficient muscle fibers secrete the fasting-induced hormone, fibroblast growth factor 21 (FGF21). This response leads to fatty acid recruitment from adipocytes and resistance to high-fat-diet induced obesity in mice, but does not affect glucose or insulin metabolism. FGF21 is also induced in the muscle of mitochondrial myopathy patients and in other RC-deficient mice. These data show that skeletal muscle is an endocrine organ, which signals its energy deficiency through FGF21. Furthermore, RC deficiency in single muscle fibers initiates a global starvation response. These data have important implications for conditions with primary or secondary RC deficiency. Mice overexpressing mutant Twinkle (C10ORF2) protein are the first animal model for Progressive External Ophtalmoplegia (PEO). Using PEO-model and wt-mice, skeletal muscle (quadriceps femoris) was analyzed for gene expression profile.
2011-11-16 | E-GEOD-18119 | biostudies-arrayexpress
Project description:To elucidate the signalling network responsible for mediating the effects of FGF21, we quantified the dynamic phosphoproteome of adipocytes following acute exposure to this hormone. A major FGF21-regulated signalling node was mTORC1/S6K. In contrast to insulin, we find that FGF21 activates mTORC1 via MAPK signalling rather than through the canonical PI3K/AKT pathway. This study provides a systems view of FGF21 signalling and reveals a new role for mTORC1 in maintaining nutrient homeostasis.
2016-08-15 | PXD003631 | Pride
Project description:Progressive mitochondrial respiratory chain (RC) deficiency is associated with a wide spectrum of adult-onset degenerative diseases, as well as with normal aging. We have previously generated the Deletor mice to model late-onset progressive RC defects. Here we report novel tissue-specific pathways contributing to mitochondrial disease pathogenesis, identified by gene expression analysis. We found that RC-deficient muscle fibers secrete the fasting-induced hormone, fibroblast growth factor 21 (FGF21). This response leads to fatty acid recruitment from adipocytes and resistance to high-fat-diet induced obesity in mice, but does not affect glucose or insulin metabolism. FGF21 is also induced in the muscle of mitochondrial myopathy patients and in other RC-deficient mice. These data show that skeletal muscle is an endocrine organ, which signals its energy deficiency through FGF21. Furthermore, RC deficiency in single muscle fibers initiates a global starvation response. These data have important implications for conditions with primary or secondary RC deficiency.
2011-11-16 | GSE18119 | GEO
Project description:Fibroblast growth factor 21 (Fgf21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting-feeding. The Sel1LHrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)- associated degradation (ERAD) machinery. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1LHrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh, while having no effect on the other well-known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L-Hrd1 ERAD and Crebh-Fgf21 levels under fasting-feeding and growth. This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERADCrebh- Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.
2018-08-17 | GSE118658 | GEO
Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions. Wildtype male mice and FGF21-knockout male mice, together with muscle specific UCP1-transgenic male animals, and double cross of FGF21-KO with UCP1-Tg male mice, were kept on a standardized low fat diet for 40 weeks. After sacrifice, subcutaneous white adipose tisseu (scWAT) was rapidly removed, weighed, and snap frozen in liquid nitrogen and used for RNA isolation and whole genome gene expression microarray hybridisation using Agilent arrays.
2016-01-07 | E-GEOD-71749 | biostudies-arrayexpress
Project description:FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation. Three mouse strains (C57BL6 on chow diet, C57BL6 on high fat diet, and db/db on chow diet) were treated with either vehicle, wild-type FGF21, or pegylated FGF21 acutely or for several days and three white adipose tissues (IWAT, EWAT, RPWAT) and brown adipose tissue (BAT) were profiled on custom Affymetrix microarrays. The primary goal was to identify robust and consistent acute target engagement biomarkers of FGF21 activation in white adipose tissues.
2013-11-18 | E-GEOD-44095 | biostudies-arrayexpress
Project description:Background. Juvenile hormone (JH) has been demonstrated to control adult lifespan in a number of non-model insects where surgical removal of the corpora allata eliminates the source of hormone. In contrast, little is known about how juvenile hormone affects adult Drosophila melanogaster. Previous work suggests that insulin signaling may modulate Drosophila aging in part through its impact on juvenile hormone titer, but no data yet addresses whether reduction of juvenile hormone is sufficient to control Drosophila life span. Here we adapt a recent genetic approach to knock out the corpora allata in adult Drosophila melanogaster and characterize adult life history phenotypes produced by reduction of juvenile hormone. With this system we test potential explanations for how juvenile hormone modulates aging. Conclusions. Reduced juvenile hormone alone is sufficient to extend lifespan of Drosophila melanogaster. Reduced juvenile hormone limits reproduction by inhibiting the production of yolked eggs, and this may arise because juvenile hormone is required for the post-eclosion development of vitellogenin-producing adult fat body. Our data do not support a mechanism for juvenile hormone control of longevity simply based on reducing the physiological costs of reproductive. Nor does the longevity benefit appear to function through mechanisms by which dietary restriction extends longevity. We identify transcripts that change in response to juvenile hormone independent of reproductive state and suggest these represent somatically expressed genes that could modulate how juvenile hormone controls persistence and longevity. Four genotypes were analyzed. They are CA knockout (CAKO), wildtype (wDah/w1118 ), CAKO with OvoD1 mutation and control (wDah/w1118) with OvoD1 mutation. Three biological replicates for each genotype.
2013-07-26 | E-GEOD-48145 | biostudies-arrayexpress
Project description:Thyroid hormone (TH) influences metabolic pathways by binding to specific receptors (TRs), which are conditional transcription factors. T3 works through TRs to induce fibroblast growth factor (FGF) 21, a peptide hormone that is usually induced in fasting and influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While administered TH and FGF21 display overlapping actions, including reductions in serum lipids, current models suggest that these hormones act independently in vivo. Here, we examined mechanisms of TH regulation of FGF21 expression and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (T3) and the TRβ selective thyromimetic GC-1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles in wild type and FGF21 knockout mice are highly similar indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously involved in T3-dependent hepatic lipid and carbohydrate metabolic processes. Accordingly, T3-dependent effects upon serum lipids are maintained in the FGF21-/- background. Our findings suggest that T3 regulates genes involved in classical hepatic metabolic responses independently of FGF21.
2014-12-31 | GSE58062 | GEO
Project description:Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine hormone that functions to regulate energy homeostasis and macronutrient intake. Recently, FGF21 was reported to be produced and secreted from hypothalamic tanycytes, to regulate peripheral lipid metabolism. However, rigorous investigation of FGF21 expression in the brain has yet to be accomplished. Utilizing a novel mouse model that drives CRE recombinase in FGF21-expressing cells, we demonstrate that FGF21 is not expressed in the hypothalamus, but instead is produced from the retrosplenial cortex (RSC), an essential brain region for spatial learning and memory. Furthermore, we find that central FGF21 produced in the RSC enhances spatial memory but does not regulate energy homeostasis or sugar intake. Finally, our data demonstrate that administration of FGF21 prolongs the duration of long-term potentiation in the hippocampus and enhances activation of hippocampal neurons. Thus, endogenous and pharmacological FGF21 appear to function in the hippocampus to strengthen the formation of spatial memory.
2022-08-23 | GSE208083 | GEO