Liver FGF21 mediates sex-specific adaptation to juvenile protein malnutrition
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE302336 | GEO | 2025/07/16
REPOSITORIES: GEO
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Project description:Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production, and retards growth. In order to identify new molecules involved in such changes, we conducted DNA microarray analysis for liver samples of rats fed isoenergetic low protein diet for 8 hours, and identified fibroblast growth factor 21 (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0.05, FDR<0.001). In addition, amino acid deprivation from the culture media increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0.01). Thus, it was suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. Using transgenic mice, FGF21 has also been shown to promote a growth hormone-resistant state and suppress IGF-I. Therefore, to further determine whether the up-regulation of Fgf21 under protein malnutrition causes hepatic steatosis and growth retardation following decrease in IGF-I, we fed isoenergetic low protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration of mice fed the low-protein diet. Meanwhile, Fgf21-KO mice showed greater epididymal white adipose tissue weight as well as hepatic triglyceride and cholesterol levels under protein malnutrition (P<0.05). Taken together, we showed that protein deprivation directly increases Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression under protein malnutrition. Furthermore, up-regulated FGF21 rather appears to have a protective effect against obesity and hepatic steatosis in protein malnourished animals. Livers of rats from 2 groups (control (15P) or low-protain (5P) diet fed groups), total of 6 samples (3 replicates for each group) were analyzed.
2015-01-15 | E-GEOD-64970 | biostudies-arrayexpress
Project description:Mammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing revealed that food restriction modulated canonical, energy-regulating pathways including oxidative phosphorylation, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling, significantly in males but not in females V1. Moreover, we found that in contrast to males, food restriction in females non-significantly affected V1 ATP usage and visual coding precision (assessed by orientation selectivity). Decreased serum leptin is necessary for triggering energy-saving changes in male mouse V1 during food restriction. Consistent with this result, we found a significant decrease of serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to metabolic challenge.
2023-10-09 | GSE233435 | GEO
Project description:Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARalpha challenge demonstrated the dysregulation of PPARalpha signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21â??s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver. Male C57Bl/6J mice were divided to 3 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR) and medium fat (MF; AIN-93W-MF; 25% energy from fat). Dietary interventions started at the age of 9 weeks and sacrifice was performed at the age of 6, 12, 24 and 28 months. We performed various measurements on metabolic parameters and gene expression analysis. This entry represents the microarray data.
2016-08-09 | E-GEOD-84495 | biostudies-arrayexpress
Project description:Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production, and retards growth. In order to identify new molecules involved in such changes, we conducted DNA microarray analysis for liver samples of rats fed isoenergetic low protein diet for 8 hours, and identified fibroblast growth factor 21 (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0.05, FDR<0.001). In addition, amino acid deprivation from the culture media increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0.01). Thus, it was suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. Using transgenic mice, FGF21 has also been shown to promote a growth hormone-resistant state and suppress IGF-I. Therefore, to further determine whether the up-regulation of Fgf21 under protein malnutrition causes hepatic steatosis and growth retardation following decrease in IGF-I, we fed isoenergetic low protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration of mice fed the low-protein diet. Meanwhile, Fgf21-KO mice showed greater epididymal white adipose tissue weight as well as hepatic triglyceride and cholesterol levels under protein malnutrition (P<0.05). Taken together, we showed that protein deprivation directly increases Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression under protein malnutrition. Furthermore, up-regulated FGF21 rather appears to have a protective effect against obesity and hepatic steatosis in protein malnourished animals.
2015-01-15 | GSE64970 | GEO
Project description:The liver plays a central role in vertebrate glucose homeostasis, and is also one of the most sexually dimorphic organs in terms of gene expression. While the extent of hepatic sexual dimorphism has been well described in mammals, little is known regarding this phenomenon in non-mammalian species, particularly fish. In this study, we examined hepatic gene expression and physiological phenotypes (growth, proximate body composition, retention efficiencies) to determine whether male and female zebrafish respond differently to diets comprised of 0, 15, 25, or 35 % carbohydrate. Using both Affymetrix microarrays and qRTPCR, we observed substantial sexual dimorphism in the hepatic transcriptome, and the response of some genes to dietary carbohydrate manipulation also varied by sex. Males upregulated genes associated with oxidative metabolism, carbohydrate metabolism, energy production, and amelioration of oxidative stress, while females had higher expression levels of genes associated with translation. Males also expressed elevated levels of hnf4α, a gene thought to be involved in regulating hepatic sexual dimorphism in the rodent. Dietary carbohydrate affected hepatic gene expression, growth performance, retention efficiencies of protein and energy, and percentage of moisture, lipid, and ash. Significant diet effects reflected differences between the 0% carbohydrate diet and the other diets, consistent with previous work on other cyprinids showing a high tolerance for dietary carbohydrate. Our data support the use of the zebrafish as a model for the study of both normal and disease states associated with carbohydrate metabolism, and highlight the importance of accounting for both sex and diet; The liver plays a central role in vertebrate glucose homeostasis, and is also one of the most sexually dimorphic organs in terms of gene expression. While the extent of hepatic sexual dimorphism has been well described in mammals, little is known regarding this phenomenon in non-mammalian species, particularly fish. In this study, we examined hepatic gene expression and physiological phenotypes (growth, proximate body composition, retention efficiencies) to determine whether male and female zebrafish respond differently to diets comprised of 0, 15, 25, or 35 % carbohydrate. Using both Affymetrix microarrays and qRTPCR, we observed substantial sexual dimorphism in the hepatic transcriptome, and the response of some genes to dietary carbohydrate manipulation also varied by sex. Males upregulated genes associated with oxidative metabolism, carbohydrate metabolism, energy production, and amelioration of oxidative stress, while females had higher expression levels of genes associated with translation. Males also expressed elevated levels of hnf4α, a gene thought to be involved in regulating hepatic sexual dimorphism in the rodent. Dietary carbohydrate affected hepatic gene expression, growth performance, retention efficiencies of protein and energy, and percentage of moisture, lipid, and ash. Significant diet effects reflected differences between the 0% carbohydrate diet and the other diets, consistent with previous work on other cyprinids showing a high tolerance for dietary carbohydrate. Our data support the use of the zebrafish as a model for the study of both normal and disease states associated with carbohydrate metabolism, and highlight the importance of accounting for both sex and diet Experiment Overall Design: 17 samples are analyzed from a factorial combination of sex (male or female) and dietary treatment (0% or 25% dietary carbohydrate). 5 biological replicates for females fed each diet, and 3 or 4 biological replicates for males fed the 0% and 25% diets, respectively.
2008-06-16 | E-GEOD-8856 | biostudies-arrayexpress
Project description:Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a new molecular circuit that regulates chondrogenic cell maintenance and output and reveals a novel, hitherto unrecognized function of IL-6 cytokines in the skeletal system with direct implications for skeletal development and regeneration.
2022-02-08 | GSE188353 | GEO
Project description:Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a new molecular circuit that regulates chondrogenic cell maintenance and output and reveals a novel, hitherto unrecognized function of IL-6 cytokines in the skeletal system with direct implications for skeletal development and regeneration.
2022-02-08 | GSE184406 | GEO
Project description:Recent studies have shown that FGF21 is a common target for dietary polyphenol intervention and nutritional restriction. FGF21 is also a newly recognized target of GLP-1R agonists (GLP-1RAs). Here we ask whether hepatic FGF21 is required for dietary polyphenols in exerting their metabolic beneficial effects. Liver-specific FGF21 null mice (lFgf21-/-) were utilized in current study. We found that on chow diet, no appreciable defect on glucose disposal was observed in male or female lFgf21-/- mice, while fat tolerance was impaired in male but not female lFgf21-/- mice, associated with elevated serum TG level, reduced hepatic expression of Ehhadh and Ppargc1. On high-fat-high-fructose (HFHF) diet challenge, Fgf21fl/fl mice but not lFgf21-/- mice exhibited response to curcumin intervention on reducing body weight and serum TG, and on improving fat tolerance. Resveratrol intervention also affected hepatic FGF21 expression and its downstream effectors. Metabolic beneficial effects of resveratrol intervention observed in HFHF diet challenged Fgf21fl/fl mice were either absent or attenuated in lFgf21-/- mice. Thus, hepatic FGF21 is required for curcumin and resveratrol in exerting their metabolic beneficial effect. Recognition that FGF21 is the common target of GLP-1RAs and dietary intervention brings us a novel angle in studying metabolic disease treatment and prevention.
2023-12-15 | GSE241713 | 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: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