FGF21 in UCP1-deficient mice
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ABSTRACT:
PROVIDER: PRJEB28632 | ENA |
REPOSITORIES: ENA
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Project description:Global RNA sequencing analysis of brown fat (BAT), inguinal white fat (iWAT), liver and muscle (quadriceps) of high-fat diet fed WT, FGF21 KO, UCP1 KO and UCP1/FGF21 double KO mice.
2019-11-05 | GSE122167 | GEO
Project description:Global RNA sequencing analysis of the hypothalamus, BAT, inguinal WAT and muscle of long-term cold exposed WT, FGF21 KO, UCP1 KO and UCP1/FGF21 double KO mice
2017-08-16 | GSE99412 | 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: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:Impact of UCP1 and FGF21 for the development of diet-induced obesity at standard housing temperatures
| PRJNA503857 | ENA
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: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:Coenzyme Q is an essential component of mitochondrial function and required for thermogenic activity in brown adipose tissues (BAT). BAT CoQ deficiency (50-75%) by genetic or pharmacological means does not interfere with basal or maximal mitochondrial respiration in brown adipocytes but increases mitochondrial oxidants and induces UPRmt, ISR, and repression of UCP1 expression. ATF4, the master regulator of ISR, is required for UCP1 suppression in BAT CoQ deficiency. In animals, BAT CoQ deficiency causes cold intolerance but activates compensatory thermogenic mechanisms in BAT and other tissues via greatly induced BAT FGF21 expression resulting in paradoxically upregulated whole-body respiration rates and protection from obesity at room temperature and thermoneutrality. BAT-specific loss of either ATF4 or FGF21 abolishes these metabolic benefits demonstrating a central role for CoQ in the modulation of whole-body energy expenditure and thus for the etiology of primary and secondary CoQ deficiencies.
2022-02-01 | GSE165940 | GEO
Project description:Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the roles of classical brown and beige adipocytes, increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to analyze transcriptome of wild type and UCP1-null beige adipocyte to identify the UCP1-independent function.
2017-10-28 | E-MTAB-4085 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide and is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signaling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic utility of brown and beige adipocytes, and UCP1, extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
2022-02-17 | PXD024717 | Pride