The hepatic transcriptome of liver-specific insulin receptor knockout (LIRKO) mouse offspring
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ABSTRACT:
PROVIDER: PRJNA591946 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10539933_1.fastq.gz | Fastqsanger.gz | |||
| SRR10539933_2.fastq.gz | Fastqsanger.gz | |||
| SRR10539934_1.fastq.gz | Fastqsanger.gz | |||
| SRR10539934_2.fastq.gz | Fastqsanger.gz | |||
| SRR10539935_1.fastq.gz | Fastqsanger.gz |
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Project description:At 2 months of age, liver-specific insulin receptor knockout (LIRKO) mice present hyperglycemia and hyperinsulinemia. Furthermore, LIRKO mice have increased levels of hepatic cholesterol. Indeed, many changes seen in cholesterol metabolism in LIRKO mice are also observed in humans with metabolic syndrome. For example, both show decreased levels of HDL and increased secretion of apoB and VLDL. These findings make the LIRKO mouse a unique non-dietary model of insulin resistant, hyperglycemia, dyslipidemia and atherosclerosis that resembles several clinical features of the human metabolic syndrome. By hepatic transcriptomic analysis of the wild-type (WT) offspring of LIRKO mice, we identify that members of the TGF-β family are differentially expressed in the offspring, including the NREP and GDF15.
2021-01-04 | GSE141077 | GEO
Project description:The hepatic methylome of liver-specific insulin receptor knockout (LIRKO) mouse offspring
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Project description:Liver-specific insulin receptor knockout (LIRKO) mouse is a unique non-dietary model of insulin resistant, hyperglycemia, dyslipidemia and atherosclerosis that resembles several clinical features of the human metabolic syndrome. By enhanced reduced representation bisulfite sequencing (ERRBS) analysis of the livers of wild-type (WT) offspring of LIRKO mice, we identified that genes with differential DNA methylation were enriched for cholesterol synthesis, MAPK, AKT, insulin and TGF-β signaling, including the NREP and GDF15.
2021-01-04 | GSE141379 | GEO
Project description:Background: Assisted Reproductive Technologies (ART) - treatments to allow parenthood to couples facing fertility issues- have allowed the birth of > 5 million babies worldwide. Notwithstanding most of ART children are healthy at birth, several studies reported that ART may affect early-life experience causing permanent changes in fetal programming and, consequently, leading to increased predisposition to metabolic disorders in adulthood. Currently, the metabolic health status of ART children has been poorly investigated and it will take decades before large-scale population studies will be implemented. Studies on animal models indicated impaired in utero development of ART conceptuses. Relevantly, our preliminary data showed hypomethylation of liver from ART foetuses, which may contribute to the fetal programming of adult diseases. Regarding adult ART offspring, obesity, glucose intolerance and lipid accumulation in the liver have been previously described in mouse model, indicative of increased risk to develop metabolic disorders. However, little is known on the pathophysiological mechanism behind the metabolic abnormalities in ART offspring. In this context, this study investigated the influence of ART on the function of the liver, a major organ involved in the maintenance of metabolic homeostasis.
Methods: To assess the influence of ART on liver functions, proteomic analysis was carried out on adult liver from 4 months old offspring developed following Embryo Transfer (ET), in vitro culture (IVC) and blastomere biopsy (BB). Control (CTR) consisted of naturally conceived offspring. Then, to verify whether and how changes in liver proteome were associated with perturbation of the metabolic status of adult offspring, general growth and physiological parameters (e.g. glucose tolerance, insulin resistance, plasmatic levels of interleukin 6, triglycerides and total cholesterol) were assessed.
Results: Proteomic analysis of adult liver showed deregulated expression of proteins involved in lipid, carbohydrate and energy metabolism as well as cellular processes in adult offspring developed following BB, IVC and ET. Characterization of metabolic phenotype of adult offspring revealed increased body weight in ART offspring, glucose intolerance in BB, IVC, ET males and BB females, insulin resistance on BB offspring, low plasmatic level of Interleukin-6 in BB, IVC, ET males and high level of triglycerides and total cholesterol in BB females vs CTR which are phenotypic manifestation of liver disfunctions and core symptoms of metabolic syndrome.
Conclusion: Our study showed DE of proteins involved in metabolic and cellular processes, indicative of impaired hepatic functions which may contribute to the onset and progression of various diseases (e.g. NASH, NAFLD, hepatocarcinoma) in mouse offspring developed following ART. Moreover, impaired hepatic metabolism was associated with obesity, glucose intolerance, insulin resistance and dyslipidaemia which are core symptoms of metabolic syndrome and risk factor for diabetes and cardiovascular diseases in adult ART offspring. Thus, we provide evidence of Assisted Reproductive Technologies is a risk factor for perturbation of hepatic proteome, associated with the increased predisposition to liver diseases and metabolic syndrome in adulthood.
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Project description:Insulin action in adipocytes affects whole-body insulin sensitivity. Studies of adipose-specific Glut4 knockout mice have established that adipose Glut4 contributes to the control of systemic glucose homeostasis. Presumably, this reflects a role for Glut4-mediated glucose transport in the regulation of secreted adipokines. In cultured 3T3-L1 adipocytes, Rab10 GTPase is required for insulin-stimulated translocation of Glut4 (Sano et al., 2007). The physiological importance of adipose Rab10 and the significance of its role in the control of Glut4 vesicle trafficking in vivo are unknown. Here we report that adipocytes from adipose-specific Rab10 knockout mice have a ~50% reduction in glucose uptake and Glut4 translocation to the cell surface in response to insulin, demonstrating a role for Rab10 in Glut4 trafficking. Moreover, hyperinsulinemic-euglycemic clamp shows decreased whole-body glucose uptake as well as impaired suppression of hepatic glucose production in adipose Rab10 knockout mice. Thus, fully functional Glut4 vesicle trafficking in adipocytes is critical for maintaining insulin sensitivity. Comparative transcriptome analysis of perigonadal adipose tissue demonstrates significant transcriptional similarities between adipose Rab10 knockout mice and adipose Glut4 knockout mice, consistent with the notion that the phenotypic similarities between the two models are mediated by reduced insulin-stimulated glucose transport into adipocytes. Transcriptome sequencing of perigonadal white adipose tissue
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Project description:The goal was to study the long term metabolic programming effects of exposure of offspring to a dam eating 60% high fat diet during the lactation period only. We previously showed that offspring from dams given lactational high fat diet (HFD) are predisposed to obesity, glucose intolerance and inflammation. The purpose of these studies was to understand the programming implications of lactational HFD on offspring metabolic liver disease risk. Dams were fed a 60% lard-based HFD from the day of delivery through the 21 day lactation period. Starting at weaning offspring were fed normal fat diet until 3 months of age at which point a subset were challenged with an additional HFD stressor. Lactational HFD fed male offspring developed hepatic insulin resistance. Postweaning HFD challenge led male offspring progressing to NAFLD with more severe outcomes in the lactational HFD challenged offspring.
2021-08-14 | GSE182071 | GEO
Project description:Understanding mechanisms causing MAFLD (Metabolic Associated Fatty Liver Disease) and its progression to MASH (metabolic dysfunction-associated steatohepatitis) is clinically important and scientifically challenging. Hepatic insulin resistance is a common component in the progression of MAFLD in patients and experimental animals; however, hepatic steatosis caused by the HFD45% (high-fat diet) decreases during chronic hepatic IR generated by inactivation of Irs1/2 (LDKO), AKT1/2, or InsR 1-3—which is inconsistent with the expected relationship between IR and MAFLD in humans4. Here we found that complete hepatic insulin resistance promotes the fructose-enriched GAN diet-induced MAFLD, including acute inflammation and MASH in LDKO mice. Unexpectedly, fructose phosphorylation catalyzed by hepatic Khk (ketohexokinase) was not required as acute MAFLD progressed strongly in LDKOKhkL/L mice fed the GAN diet. FoxO1 activated during hepatic IR induces Fst (Follistatin) expression and secretion from the liver of LDKO mice. Inactivation of hepatic FoxO1 in LTKO mice (LDKO•FoxO1L/L) or Fst in LDKOFstKO mice prevented acute MAFLD during the GAN diet. Consistently, overexpression of hepatic Fst promoted GAN diet-induced MAFLD/MASH and hepatic carcinoma. Mechanistically, circulating Fst promoted adipose tissue IR and lipolysis, which can deliver FFA (free fatty acid) to the liver for esterification with excess Gro3P (glycerol 3-phosphate) generated by fructose metabolism, although hepatic DNL (de novo lipogenesis) decreased strongly in LDKO mice while. Since circulating FST correlates positively with both T2D and MAFLD in humans, our results suggests that hepatic FST induced by progressive hepatic IR might promote MAFLD/MASH during the consumption of sugar-sweetened food and beverages consumed frequently by people and animals with T2D.
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Project description:We determined the effects of excess folic acid supplementation (5x recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of gestational dibetes (GDM; 45% kcal fat diet) and control mice (10% kcal diet) we show that folic acid supplementation increased weight gain and fat mass in both GDM and control mice but improved insulin sensitivity in GDM mice and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation may not be due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (GDM and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the offspring from supplemented dams but this differed between GDM and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype, and has sex-specific effects on offspring pancreas and liver.
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