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The roles of ppar-delta and ppar-gamma in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue

ABSTRACT: Obesity is a major risk factor for the development of insulin resistance and type II diabetes. The nuclear receptors PPAR-delta and PPAR-gamma play a central role in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. The metabolic effects of PPAR-delta and PPAR-gamma activation have been examined both in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using a combined 1H NMR spectroscopy and mass spectrometry metabolomic methodology to understand the contrasting roles of these receptors. These steady state measurements were supplemented with 13C-stable isotope substrate labeling to assess fluxes, respirometry and transcriptomic microarray analysis. The metabolic effects of the two receptors were readily distinguished, with PPAR-gamma activation characterised by increased fat storage and fat synthesis/elongation, while activation of PPAR-delta caused increased fatty acid beta-oxidation, TCA cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased desaturation of fatty acids were the only common pathways. PPAR-delta has a role as an anti-obesity target as well as an anti-diabetic.

ORGANISM(S): Mus musculus

PROVIDER: GSE26207 | GEO | 2011/07/14

SECONDARY ACCESSION(S): PRJNA135035

REPOSITORIES: GEO

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The roles of ppar-delta and ppar-gamma in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue

Project description:Obesity is a major risk factor for the development of insulin resistance and type II diabetes. The nuclear receptors PPAR delta and PPAR gamma play a central role in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. The metabolic effects of PPAR delta and PPAR gamma activation have been examined both in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using a combined 1H NMR spectroscopy and mass spectrometry metabolomic methodology to understand the contrasting roles of these receptors. These steady state measurements were supplemented with 13C-stable isotope substrate labeling to assess fluxes, respirometry and transcriptomic microarray analysis. The metabolic effects of the two receptors were readily distinguished, with PPAR gamma ?activation characterised by increased fat storage and fat synthesis/elongation, while activation of PPAR delta caused increased fatty acid beta-oxidation, TCA cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased desaturation of fatty acids were the only common pathways. PPAR delta has a role as an anti-obesity target as well as an anti-diabetic. Total RNA obtained from cultured 3T3-L1 cells treated for 48 hours with either DMSO control, GW610742 PPARd agonist or GW347845 PPARg agonist and compared.

2011-07-13 | E-GEOD-26207 | biostudies-arrayexpress

Expression profiling of pancreatic beta-cells harboring a pancreatic-specific deletion of PPAR-beta

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Okra polysaccharide activates PPAR-γ signaling to attenuate metabolic-associated fatty liver disease in mice

Project description:Okra (Abelmoschus esculentus (L.) Moench) serves as a botanical resource extensively utilized in ethnomedicine. Prior investigations revealed that okra polysaccharide (OP) ameliorated hepatocellular lipotoxicity in vitro context. Nonetheless, the curative efficacy and the precise molecular mechanisms implicated in metabolic-associated fatty liver disease (MAFLD) warrant further elucidation. To address this gap, two murine models of MAFLD, namely obese Ob/Ob mice and high fat/cholesterol/fructose (HFCF) fed mice, were employed. The therapeutic implications of OP supplementation were assessed through quantification of lipid specific biomarkers and hepatic histopathological examination. Complementary transcriptomic, phosphoproteomic, and in vitro analyses were conducted to decipher the molecular underpinnings. In the Ob/Ob mouse model, OP substantively mitigated both circulating and hepatic lipid concentrations, concurrently ameliorating hepatic steatosis. In the context of HFCF-induced MAFLD, OP not only attenuated hepatic lipidic sequestration but also abrogated concomitant inflammation and fibrosis. Subsequent RNA-sequencing analyses on hepatic tissues derived from HFCF-diet mice delineated that OP modulated MAFLD-associated transcriptional signatures. A synergistic assessment of transcriptomics and phosphoproteomics disclosed a salient effect of OP on the Peroxisome Proliferator-Activated Receptor (PPAR) pathway, particularly manifested by the upregulation of PPAR-γ signaling. In murine hepatocytes, OP counteracted steatosis and inflammation via the activation of PPAR-γ signaling. The effects induced by OP were nullified upon administration of the PPAR-γ-specific antagonist GW9662. Collectively, our empirical evidence furnishes the inaugural demonstration that OP mitigates MAFLD pathology through the activation of PPAR-γ signaling, thereby presenting a novel therapeutic avenue for MAFLD intervention.

2024-08-21 | GSE273255 | GEO

Nordihydroguaiaretic Acid Improves Metabolic Dysregulation and Aberrant Hepatic Lipid Metabolism in Mice by Both PPAR-alpha-Dependent and -Independent Pathways

Project description:To test whether NDGA attenuate dyslipidemia and hepatic steatosis by enhancing fatty acid oxidation through activation of PPAR-α. Using wild type (WT, C57BL/6) fed with chow diet as control, WT mice were either fed with high-fat diet or high-fat diet with NDGA (2.5g/kg food); ob/ob mice were fed with either chow or chow with NDGA (2.5 g/kg food), and maintained on the respective diets for 16 weeks. The expression of lipid metabolism related genes in the liver of these mice were analyzed using Phalanx GPL6845 platform (Mouse OneArray V1). Together with other biochemical/physiological data, our results suggest that the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation and energy utilization via the activation of PPAR- α receptor activity.

2012-03-30 | GSE35075 | GEO

The Plant-derived Lipoxygenase Inhibitor Nordihydroguaiaretic Acid (NDGA) Attenuates Dyslipidemia and Hepatic Steatosis by Enhancing Fatty Acid Oxidation through Activation of PPAR-alpha

2012-03-29 | E-GEOD-35075 | biostudies-arrayexpress

Expression profiling of pancreatic beta-cells harboring a pancreatic-specific deletion of PPAR-beta

2012-08-30 | E-GEOD-16048 | biostudies-arrayexpress

Identification of an alternative ligand binding pocket in PPAR-γ and its corelated selective agonist for promoting beige adipocyte differentiation

Project description:Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) is a convenient and promising tactic for promoting beige adipocyte biogenesis to combat obesity-related metabolic disorders. However, thiazolidinediones (TZDs), the full agonist of PPAR-γ exhibits severe side effects in animal model and clinical uses. Therefore, it is emerging to develop efficient and safe PPAR-γ modulators for metabolic disease treatment. Here, by utilizing comprehensive methods, we report a previously unidentified ligand binding pocket (LBP) in PPAR-γ and link it to beige adipocyte differentiation. Further virtual screening from 4097 natural compounds based on this novel LBP, we discover NJT-2, a terpenoid compound, can bind to PPAR-γ induce co-activator recruitment and effectively activate PPAR-γ mediated transcription of beige adipocyte program. Importantly, in mouse model, NJT-2 administration efficiently promotes beige adipocyte biogenesis and improve obesity-associated metabolic dysfunction with significant lower adverse effects than those observed in TZD. Our results not only provide an advanced molecular insight into the structural ligand binding details in PPARg, but also develop its linked selective and safe agonist for obesity treatment.

2024-05-21 | GSE267657 | GEO

The histone methyltransferases Suv420h regulate PPAR-γ and energy expenditure in response to environmental stimuli

Project description:The rising prevalence of obesity and its associated metabolic abnormalities have become global diseases that carry considerable morbidity and mortality. While there is certainly an important genetic component, extensive human epidemiologic and animal model data suggest an epigenetic component to obesity. Nevertheless, the cellular and molecular underpinnings of these pathways and how they contribute to the development of obesity remain to be elucidated. Suv420h1 and h2 are histone methyltransferases responsible for chromatin compaction and gene repression. Through in vivo, ex-vivo and in vitro studies, we found that Suv420h1 and h2 respond to environmental stimuli and regulate metabolism by downregulating PPAR-γ, a master transcriptional regulator of lipid storage and glucose metabolism. Accordingly, mice lacking Suv420h proteins activate PPAR-γ target genes in brown adipose tissue to increase mitochondria respiration, improve glucose tolerance and reduce adipose tissue to fight obesity. We conclude that Suv420h proteins are key epigenetic regulator of PPAR-γ and the pathways controlling metabolism and weight balance in response to environmental stimuli.

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Interference with PPAR gamma signaling in mesenteric artery

Project description:Pharmacological activation of the transcription factor PPAR gamma lowers blood pressure and improves glucose tolerance in humans. In contrast, naturally occurring mutations (e.g., P467L, V290M) in the ligand binding domain of PPAR gamma in humans leads to severe insulin resistance and early-onset hypertension. Experimental evidence, including whole genome expression profiling, suggests that these mutant versions of PPAR gamma act in a dominant negative manner. Because PPAR gamma is expressed in a variety of cell types and tissues, we generated a transgenic mouse model (SP467L) specifically targeting dominant negative PPAR gamma to the vascular smooth muscle cells in order to determine the action of PPAR gamma in the blood vessel independent of its systemic metabolic actions. In the data set provided herein, we examined the gene expression profile in mesenteric vessels from SP467L mice and their control littermates using the Affymetrix mouse exon 1.0 ST array.

2012-09-24 | GSE36482 | GEO

Re-expression of GATA2 Cooperates with PPAR gamma Depletion to Revert the Adipocyte Phenotype

Project description:The nuclear receptor PPAR gamma is required for adipocyte differentiation, but its role in mature adipocytes is less clear. Here we report that knockdown of PPAR gamma expression in 3T3-L1 adipocytes returned the expression of most adipocyte genes towards preadipocyte levels. Consistently, down regulated but not up regulated genes showed strong enrichment of PPAR gamma binding. Surprisingly, not all adipocyte genes were reversed and the adipocyte morphology was maintained for an extended period after PPAR gamma depletion. To explain this, we focused on transcriptional regulators whose adipogenic regulation was not reversed upon PPAR gamma depletion. We identified GATA2, a transcription factor whose down-regulation early in adipogenesis is required for preadipocyte differentiation, remaining low after PPAR gamma knockdown. Forced expression of GATA2 in mature adipocytes complemented PPAR gamma depletion and impaired adipocyte functionality with a more preadipocyte- like gene expression profile. Ectopic expression of GATA2 in adipose tissue in vivo had similar effect on adipogenic gene expression. These results suggest that PPAR gamma-independent down regulation of GATA2 prevents reversion of mature adipocytes after PPAR gamma depletion. Keywords: cell type comparison, Gata2, PPAR gamma, adipocyte, preadipocytes, differentiation

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