A PPARγ-FGF1 axis is required for adaptive adipose remodeling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE31692 | GEO | 2012/04/23
SECONDARY ACCESSION(S): PRJNA145363
REPOSITORIES: GEO
Similar Datasets
Project description:We identify fibroblast growth factor 1 (FGF1) as a critical transducer in adipose tissue remodeling and link its regulation to peroxisome proliferator activated-receptor ? (PPAR?), the adipocyte master regulator and target of the thiazolidinedione (TZD) class of insulin sensitizing drugs. We show that FGF1 is highly induced in adipose tissue in response to high-fat diet (HFD) and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with HFD. Mechanistically, we show that transcription of FGF1 is directly regulated by an adipocyte-selective proximal PPAR response element, and that this PPAR?-FGF1 axis is evolutionarily conserved in mammals. This work describes the first phenotype of the FGF1 knockout mouse and establishes FGF1 as a new member of the NR-FGF axis critical for maintaining metabolic homeostasis and insulin sensitization. Total RNA was obtained from epidydimal white adipose tissue (eWAT) and livers from 6 month old wild-type and FGF1-/- mice after 16 weeks on normal chow or high-fat diets.
2012-04-22 | E-GEOD-31692 | biostudies-arrayexpress
Project description:Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARγ ligands. We transcriptionally profiled 364 biopsies gathered from 72 human subjects harvested before and after hyperinsulinemic-euglycemic clamp, at baseline and after three-month TZD treatment. Subjects range from insulin-sensitive to insulin-resistant. Insulin resistant subjects responded to TZD treatment with varied improvements in insulin sensitivity, thus they were ranked by their degree of TZD response to define responder and non-responder subgroups.
2010-05-17 | GSE13070 | GEO
Project description:Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPAR? ligands. We transcriptionally profiled 364 biopsies gathered from 72 human subjects harvested before and after hyperinsulinemic-euglycemic clamp, at baseline and after three-month TZD treatment. Subjects range from insulin-sensitive to insulin-resistant. Insulin resistant subjects responded to TZD treatment with varied improvements in insulin sensitivity, thus they were ranked by their degree of TZD response to define responder and non-responder subgroups. Skeletal muscle biopsies were obtained from vastus lateralis before and after hyperinsulinemic-euglycemic clamp, at baseline and after three-month TZD treatment. Adipose tissue biopsies were obtained from abdominal subcutaneous before clamp, at baseline and after three-month TZD treatment. *** CEL files not provided for 40 Samples. ***
2010-05-17 | E-GEOD-13070 | biostudies-arrayexpress
Project description:Toll-like receptors/Interleukin-1 receptor (IL-1R) signaling plays an important role in High-fat diet (HFD)-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM (IL-1R-associated kinase M)-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduced HFD-induced body weight gain, increased whole body energy expenditure and improved insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induced the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuated HFD-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a novel therapeutic target for obesity.
2022-06-09 | PXD031934 | Pride
Project description:A PPARγ-FGF1 axis is required for adaptive adipose remodeling
| PRJNA145363 | ENA
Project description:PPARγ regulates glucose and lipid homeostasis, insulin signaling and adipocyte differentiation. Here we report the skipping of exon 5 as legitimate splicing event generating PPARγΔ5, a new truncated isoform lacking the ligand binding domain. PPARγΔ5 is endogenously expressed in human adipose tissue and during adipocyte differentiation, lacks the ligand-dependent transactivation ability and acts as dominant negative reducing PPARγ activity. Ligand-mediated PPARγ activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a new mechanism regulating PPARγ activity. PPARγΔ5 over-expression modifies PPARγ-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPARγΔ5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of obese and diabetic patients. From a functional perspective, PPARγΔ5 mimics PPARG dominant negative mutated receptors, possibly contributing to adipose tissue dysfunctions. These findings open unexplored scenario in PPARG regulation and PPARγ-related diseases.
2018-10-14 | GSE120466 | 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: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: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:Fibroblast growth factor 1 (FGF1) binds to specific FGF receptors (FGFRs) at the surface of target cells to initiate intracellular signaling. In addition, FGF1 also binds to heparan sulfate proteoglycans (HSPG), which act as important co-receptors. Even if some interactions with HSPGs have been characterized, it is not entirely clear if FGF1 could interact with additional proteoglycans at the cell surface. We have devised and tested a method to identify novel binding sites for FGF1 at the cell surface, which may also be applicable for other protein ligands. First, we constructed an APEX2-FGF1 fusion protein to perform proximal biotin labeling of proteins after binding of the fusion protein to cells. After functional validation of the construct, we used this method to identify binding sites for FGF1 on living cells. We confirmed the feasibility of our approach by easy detection of FGFR4, a well-known and specific receptor for FGF1. We then performed a screen in RPE1 cells and among the top hits were the proteoglycans CSPG4 (NG2) and CD44. We found that FGF1 binds CD44 through its heparin-binding moiety. Moreover, we found that FGF1 co-localizes with both CSPG4 and CD44 at the cell surface suggesting that these receptors act as storage molecules creating a reservoir of FGF1. Importantly, our data demonstrate that recombinant ligand-APEX2 fusion proteins can be used to identify novel receptor interactions at the cell-surface.
2018-06-06 | PXD009302 | Pride