Mus musculus
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ABSTRACT:
PROVIDER: PRJNA151747 | ENA |
REPOSITORIES: ENA
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Project description:The physiological role of the spliced form of X-box-binding protein 1 (XBP1s), a key transcription factor of the endoplasmic reticulum (ER) stress response, in adipose tissue remains largely unknown. Here we show that overexpression of XBP1s promotes adiponectin multimerization in adipocytes, thereby regulating systemic glucose homeostasis. Ectopic expression of XBP1s in adipocytes improves glucose tolerance and insulin sensitivity in both lean and obese (ob/ob) mice. The beneficial effect of adipocyte XBP1s on glucose homeostasis is associated with elevated serum levels of HMW adiponectin and indeed, is adiponectin dependent. Mechanistically, XBP1s promotes adiponectin multimerization rather than activating its transcription likely through a direct regulation of the expression of several ER-chaperones involved in adiponectin maturation, including Grp78, Pdia6, ERp44 and DsbA-L. Thus, we conclude that XBP1s is an important regulator of adiponectin multimerization, which may lead to a new therapeutic approach for the treatment of type 2 diabetes and hypoadiponectinemia. Epididymal adipose tissue from wild type and XBP1-overexpressing mice was subjected to gene expression profiling.
2013-11-21 | E-GEOD-36031 | biostudies-arrayexpress
Project description:The physiological role of the spliced form of X-box-binding protein 1 (XBP1s), a key transcription factor of the endoplasmic reticulum (ER) stress response, in adipose tissue remains largely unknown. Here we show that overexpression of XBP1s promotes adiponectin multimerization in adipocytes, thereby regulating systemic glucose homeostasis. Ectopic expression of XBP1s in adipocytes improves glucose tolerance and insulin sensitivity in both lean and obese (ob/ob) mice. The beneficial effect of adipocyte XBP1s on glucose homeostasis is associated with elevated serum levels of HMW adiponectin and indeed, is adiponectin dependent. Mechanistically, XBP1s promotes adiponectin multimerization rather than activating its transcription likely through a direct regulation of the expression of several ER-chaperones involved in adiponectin maturation, including Grp78, Pdia6, ERp44 and DsbA-L. Thus, we conclude that XBP1s is an important regulator of adiponectin multimerization, which may lead to a new therapeutic approach for the treatment of type 2 diabetes and hypoadiponectinemia.
2013-11-21 | GSE36031 | GEO
Project description:We previously demonstrated that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7, the gene encoding Membrane Bound O-Acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated floxed Mboat7 mice and created hepatocyte- and adipocyte-specific knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. After chow and high fat diet feeding (60% kCal fat), mice were subjected to metabolic phenotyping and tissues to molecular workup and analysis. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ~100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.
2023-05-10 | PXD039894 | Pride
Project description:Feeding a modified fish diet has been suggested to improve insulin sensitivity in bottlenose dolphins; however insulin sensitivity was not directly measured. Since demonstrating an improvement in insulin sensitivity is technically difficult in dolphins, we postulated that directional changes in the hormone axis: fibroblast growth factor 21 (FGF21)/Adiponectin/Ceramide (Cer), could provide further support to this hypothesis. Proteomic analysis of the serum proteins revealed few changes in serum proteins over the study period. In conclusion, changing the types of fish fed to dolphins resulted in increases in the insulin sensitizing hormone adiponectin and serum sphingosines consistent with an insulin sensitizing phenotype.
2016-04-20 | PXD003425 | Pride
Project description:Background. Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. LIM Domain Only 3 (LMO3) plays a crucial role in adipogenesis modulating the key adipogenic master switch PPARγ in human, but not mouse, visceral adipose progenitors; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. Aims/Hypothesis. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Methods. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain- or loss of LMO3 expression, respectively.Results. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. Lmo3 expression in eWAT significantly improved glucose clearance and insulin sensitivity in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, Lmo3 expression in 3T3-L1 adipocytes increased insulin-stimulated GLUT4 translocation and glucose uptake as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. On a molecular level, LMO3 augmented PPARg activity, oxidative mitochondrial gene expression, which depended on and the expression of the PPARg co-activator Ncoa1, which was required for LMO3 effects on mitochondria and glucose uptake. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. Conclusions. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose tolerance, insulin sensitivity and adiponectin secretion. Together with increased PPARγ activity, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.
2021-08-24 | GSE155781 | GEO
Project description:The brain plays a key role in energy homeostasis, detecting circulating hormones from peripheral organs, nutrients, and metabolites, and integrating this information to control food intake and energy expenditure. However, the signals mediating communication between peripheral organs and brain are largely unknown. Here, we show that a group of neurons in the Drosophila larval brain expressing the adiponectin receptor (AdipoR) control systemic growth and metabolism. We identify glucose-regulated protein 78 (Grp78) as a circulating ligand for AdipoR. Grp78 is produced by fat cells in response to dietary sugar and modulates the activity of AdipoR-positive neurons. The terpenoid juvenile hormone (JH) serves as an effector for brain AdipoR signaling, reducing the levels of insulin signaling in peripheral organs. In conclusion, we identify a neuroendocrine axis whereby AdipoR neurons control systemic insulin responses by modulating peripheral JH function.
2021-06-15 | PXD013689 | Pride
Project description:Aims/Hypothesis. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Methods. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain- or loss of LMO3 expression, respectively. Results. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. Lmo3 expression in eWAT significantly improved glucose clearance and insulin sensitivity in diet-induced obesity, paralleled by increased serum adiponectin. On a molecular level, LMO3 expression in eWAT increased pathways indicative of adipogenesis and PPARg signaling as well as mitochondrial activity, paralleled by a suppression of adipose tissue fibrosis. In vitro, Lmo3 expression in 3T3-L1 adipocytes increased insulin-stimulated GLUT4 translocation and glucose uptake as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. LMO3 overexpression promoted, while silencing of LMO3 suppressed, mitochondrial oxidative capacity in human mature adipocytes. Conclusions. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose tolerance, insulin sensitivity and adiponectin secretion. Together with increased PPARγ activity, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.
2021-08-24 | GSE139155 | GEO
Project description:Aims/Hypothesis. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Methods. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain- or loss of LMO3 expression, respectively. Results. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. Lmo3 expression in eWAT significantly improved glucose clearance and insulin sensitivity in diet-induced obesity, paralleled by increased serum adiponectin. On a molecular level, LMO3 expression in eWAT increased pathways indicative of adipogenesis and PPARg signaling as well as mitochondrial activity, paralleled by a suppression of adipose tissue fibrosis. In vitro, Lmo3 expression in 3T3-L1 adipocytes increased insulin-stimulated GLUT4 translocation and glucose uptake as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. LMO3 overexpression promoted, while silencing of LMO3 suppressed, mitochondrial oxidative capacity in human mature adipocytes. Conclusions. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose tolerance, insulin sensitivity and adiponectin secretion. Together with increased PPARγ activity, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.
2021-08-24 | GSE139162 | GEO
Project description:Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we have investigated the role of phosphatase binding protein Alpha4 (α4) that is essential for the Ser/Thr protein phosphatase PP2A in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated Ser/Thr phosphorylation despite a decrease in the PP2A levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor Tyr phosphorylation. This occurs through decreased association of α4 with Y-box protein 1 (YBX1), resulting in the enhancement of the Tyr phosphatase PTP1B expression. Moreover, adipocyte-specific knockout of α4 results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /YBX1-mediated pathway of insulin receptor signaling is essential for maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.
2022-09-21 | GSE210407 | GEO
Project description:The goal of this study is to understand the role of adipocyte-specific Trib1 in adiponectin and plasma lipid regulation. Here, we report that adipocyte-specific Trib1 knockout mice (Trib1_ASKO) have increased plasma adiponectin levels and decreased plasma cholesterol and triglycerides. We demonstrate that loss of Trib1 increases adipocyte production and secretion of adiponectin independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice suggests that alterations in adipocyte function underlie the plasma lipid changes observed in these mice. Secretomics and RNA-seq analysis revealed that Trib1_ASKO mice have increased production of Lpl and decreased production of Angptl4 in adipose tissue, and fluorescent substrate assays confirm an increase in adipose tissue Lpl activity, which likely underlies the observed triglyceride phenotype. In summary, we demonstrate here a novel role for adipocyte Trib1 in regulating plasma adiponectin, total cholesterol, and triglycerides in mice, confirming previous genetic associations observed in humans and providing a novel avenue through which Trib1 regulates plasma lipids and coronary artery disease.
2022-06-30 | GSE168596 | GEO