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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

Project description:Peroxisome proliferator-activated receptor beta/delta protects against obesity by reducing dyslipidemia and insulin resistance via effects in various organs, including muscle, adipose tissue, liver, and heart. However, nothing is known about the function of PPAR-beta in pancreas, a prime organ in the control of glucose metabolism. To gain insight into so far hypothetical functions of this PPAR isotype in insulin production, we specifically ablated Ppar-beta in pancreas. The mutated mice developed a chronic hyperinsulinemia, due to an increase in both beta-cell mass and insulin secretion. Gene expression profiling indicated a broad repressive function of PPAR-beta impacting the vesicular compartment, actin cytoskeleton, and metabolism of glucose and fatty acids. Analyses of insulin release from the islets revealed an increased second-phase glucose-stimulated insulin secretion. Higher levels of PKD, PKC-delta and diacyglycerol in mutated animals lead to an enhanced formation of trans-Golgi network (TGN)-to-plasma-membrane transport carriers in concert with F-actin disassembly, which resulted in increased insulin secretion and its associated systemic effects. Taken together, these results provide evidence for PPAR-beta playing a repressive role on beta-cell growth and insulin exocytosis, which shed new light on its anti-obesity action.

2012-08-30 | GSE16048 | 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

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.

2019-04-23 | GSE117482 | GEO

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

2009-01-14 | GSE14004 | GEO

PPAR[gamma]2 exerts a tumor suppressive effect in human prostate cancer

Project description:The nuclear receptor PPAR[gamma] is a master regulator controlling energy metabolism and cell fate in the prostate. One advanced human prostate cancer cell line PC3 was used to examine the effects of restoration of PPAR[gamma]2 action. Restoration of PPAR[gamma]2 action in PC3 cells inhibited cell proliferation and migration. PC3-PPAR[gamma]2 cDNA recombinants showed necrosis in cancer region and lymphocyte infiltration in surrounding stroma by H&E staining. They expressed low microtubules associated protein 1 light chain 3 (LC3), and high mixed lineage kinase domain-like (MLKL), CD4 and CD8 protein expression levels compare to the control by IHC staining. Gain-of-function of PPAR[gamma]2 in PC3 cells resulted in reprogramming of lipid and energy metabolism-associated signaling pathways by microarray analysis. These data are consistent with the idea that PPAR[gamma] action specific to PPAR[gamma]2, exerts a crucial tumor suppressive role on triggering autophagy and necroptosis in human prostate cancer initiation and progression.

2020-12-10 | GSE108309 | GEO

Macrophagic S100A4 drives macrophage protumor activation and promotes tumor growth through controlling PPAR-γ induction

Project description:The lipid-metabolism up-regulation-mediated M2 polarization provides tumor-associated macrophages (TAMs) with protumor phenotypes during tumor development and progression. However, how TAMs reprogram their lipid-metabolism responding to M2 activators remains unclear. Here, we report that S100A4 is a determinant of macrophage M2 polarization. We find that the growth of carcinoma grafts was impaired in myeloid S100A4-deficient mice. Coincidentally, ablating S100A4 in macrophages reduced their capability of macrophage into utilization utilize of exogenous fatty acids as their major energy source for oxidation. Mechanistic analysis demonstrates that the induction of PPAR-γ responding to Th2 cytokine, IL-4, was halted in s100a4-deleted TAMs, as well as in bone marrow-derived macrophages, and as well as in Raw264.7 cells. Further molecular analyses reveal that CD36, downstream from S100A4-PPARγ, is the major effector for lipid uptake of S100A4+ macrophages. FurthermoreImportantly, higher levels of S100A4 is closely associated with tumor resistance to chemotherapy in murine models as well as poor prognosis of cancer patients in clinic . Our study thus suggests that blocking S100A4 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting PPAR-γ-induction mediated gene up-regulation.

2021-06-30 | GSE161060 | GEO

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