Sex differences in FGF21-induced changes in hepatic metabolism
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ABSTRACT:
PROVIDER: PRJNA867142 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20955635.fastq.gz | Fastqsanger.gz | |||
| SRR20955636.fastq.gz | Fastqsanger.gz | |||
| SRR20955637.fastq.gz | Fastqsanger.gz | |||
| SRR20955638.fastq.gz | Fastqsanger.gz | |||
| SRR20955639.fastq.gz | Fastqsanger.gz |
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Project description:To investigate sex-dependent changes in hepatic metabolism in response to fibroblast growth factor-21 (FGF21), we administered FGF21 or vehicle to mice on a high-fat diet then performed gene expression profiling analysis using data obtained from RNA-seq from livers of male and female mice.
2022-08-22 | GSE210683 | GEO
Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.
2022-03-10 | PXD025268 | Pride
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:Dietary protein sufficiency during childhood is essential for healthy growth and tissue development. Chronic protein deficiency leads to stunting, height-for-age more than two standard deviations below the median, and affects 149 million children under five (https://www.who.int/publications/i/item/9789240073791). Linear growth is governed by the somatotropic axis, wherein pituitary growth hormone (GH) stimulates hepatic insulin-like growth factor 1 (IGF-1) to promote bone elongation1. Although boys are consistently more stunted than girls across populations (ranging from 18% to 45%)2,3, mechanisms underlying this apparent resilience remain unclear. Rodent studies suggest that the protein-to-carbohydrate ratio modulates life-history traits such as metabolism, lifespan, and reproduction, with evidence of sex-dependent sensitivity4,5. Whether such dimorphism reflects coordinated developmental adaptations in response to protein scarcity, particularly in females, has not been fully explored. Here, we show that juvenile dietary protein restriction causes sexually dimorphic adaptations with pronounced stunting in males and delayed reproductive maturation in females. Using liver-specific deletion, we identify fibroblast growth factor 21 (FGF21) as a sex-specific hepatic regulator of female somatic growth and reproductive development, revealing a dimorphic endocrine adaptation to early-life protein scarcity. Our findings position FGF21 as a critical metabolic checkpoint coordinating growth and reproductive timing in response to nutritional stress.
2025-07-16 | GSE302336 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE23808: Molecular studies on sex-different control of the hepatic metabolism in relations to insulin sensitivity (set 1) GSE23809: Molecular studies on sex-different control of the hepatic metabolism in relations to insulin sensitivity (set 2) Refer to individual Series
2011-08-09 | E-GEOD-23810 | biostudies-arrayexpress
Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARto transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and KL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals
2020-05-26 | PXD015672 | Pride
Project description:Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step in the development of NAFLD. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism to NAFLD and systemic metabolic homeostasis. We show that LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress and damage in response to high fat diets. Furthermore, increased energy expenditure accompanied by enhanced adipose tissue browning was observed in LKO mice. Mechanistically, hepatic CPT1A deficiency actives the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis and the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Thus, our study demonstrates that liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
2022-09-10 | GSE183650 | GEO
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:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARa to transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and bKL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.
2019-10-01 | GSE138157 | GEO
Project description:The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating PPARa-dependent expression of the hepatokine FGF21. Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encodes JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2a and JNK2b. Here we demonstrate that Fgf21 gene expression and metabolic regulation is primarily regulated by the JNK2a isoform. To identify relevant substrates of JNK2a, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK-deficiency in hepatocytes, and mice that express only JNK2a or JNK2b in hepatocytes. We identified the JNK substrate RXRa as a protein that exhibited JNK2a-promoted phosphorylation in vivo. RXRa functions as a heterodimeric partner of PPARa and may therefore mediate the effects of JNK2a signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRa proteins. We found that the RXRa phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.
2022-10-12 | PXD034183 | Pride