gw0742 and Obesity

gw0742 has been researched along with Obesity* in 5 studies

Other Studies

5 other study(ies) available for gw0742 and Obesity

ArticleYear
Complementary Immunometabolic Effects of Exercise and PPARβ/δ Agonist in the Context of Diet-Induced Weight Loss in Obese Female Mice.
    International journal of molecular sciences, 2019, Oct-19, Volume: 20, Issue:20

    Regular aerobic exercise, independently of weight loss, improves metabolic and anti-inflammatory states, and can be regarded as beneficial in counteracting obesity-induced low-grade inflammation. However, it is still unknown how exercise alters immunometabolism in a context of dietary changes. Agonists of the Peroxisome Proliferator Activated-Receptor beta/delta (PPARβ/δ) have been studied this last decade as "exercise-mimetics", which are potential therapies for metabolic diseases. In this study, we address the question of whether PPARβ/δ agonist treatment would improve the immunometabolic changes induced by exercise in diet-induced obese female mice, having switched from a high fat diet to a normal diet. 24 mice were assigned to groups according to an 8-week exercise training program and/or an 8-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist. Our results show metabolic changes of peripheral lymphoid tissues with PPARβ/δ agonist (increase in fatty acid oxidation gene expression) or exercise (increase in AMPK activity) and a potentiating effect of the combination of both on the percentage of anti-inflammatory Foxp3+ T cells. Those effects are associated with a decreased visceral adipose tissue mass and skeletal muscle inflammation (TNF-α, Il-6, Il-1β mRNA level), an increase in skeletal muscle oxidative capacities (citrate synthase activity, endurance capacity), and insulin sensitivity. We conclude that a therapeutic approach targeting the PPARβ/δ pathway would improve obesity treatment.

    Topics: Animals; Diet, High-Fat; Energy Metabolism; Female; Glucose; Insulin Resistance; Lipid Metabolism; Lymphocyte Count; Mice; Mice, Obese; Muscle, Skeletal; Obesity; Physical Conditioning, Animal; PPAR delta; PPAR-beta; T-Lymphocytes, Regulatory; Thiazoles; Weight Loss

2019
Chronic peroxisome proliferator-activated receptorβ/δ agonist GW0742 prevents hypertension, vascular inflammatory and oxidative status, and endothelial dysfunction in diet-induced obesity.
    Journal of hypertension, 2015, Volume: 33, Issue:9

    Endothelial dysfunction plays a key role in obesity-induced risk of cardiovascular disease. The aim of the present study was to analyze the effect of chronic peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW0742 treatment on endothelial function in obese mice fed a high-fat diet (HFD).. Five-week-old male mice were allocated to one of the following groups: control, control-treated (GW0742, 3 mg/kg per day, by oral gavage), HFD, HFD + GW0742, HFD + GSK0660 (1 mg/kg/day, intraperitoneal) or HFD-GW0742-GSK0660 and followed for 11 or 13 weeks. GW0742 administration to mice fed HFD prevented the gain of body weight, heart and kidney hypertrophy, and fat accumulation. The increase in plasma levels of fasting glucose, glucose tolerance test, homeostatic model assessment of insulin resistance, and triglyceride found in the HFD group was suppressed by GW0742. This agonist increased plasma HDL in HFD-fed mice and restored the levels of tumor necrosis factor-α and adiponectin in fat. GW0742 prevented the impaired nitric oxide-dependent vasodilatation induced by acetylcholine in aortic rings from mice fed HFD. Moreover, GW0742 increased both aortic Akt and endothelial nitric oxide synthase phosphorylation, and inhibited the increase in caveolin-1/endothelial nitric oxide synthase interaction, ethidium fluorescence, NOX-1, Toll-like receptor 4, tumor necrosis factor-α, and interleukin-6 expression, and IκBα phosphorylation found in aortae from the HFD group. GSK0660 prevented all changes induced by GW0742.. PPARβ/δ activation prevents obesity and exerts protective effects on hypertension and on the early manifestations of atherosclerosis, that is, endothelial dysfunction and the vascular pro-oxidant and pro-inflammatory status, in HFD-fed mice.

    Topics: Adiponectin; Adipose Tissue; Animals; Aorta; Blood Glucose; Caveolin 1; Diet, High-Fat; Endothelium, Vascular; Glucose Tolerance Test; Hypertension; Insulin Resistance; Interleukin-6; Male; Mice; Nitric Oxide Synthase Type III; Obesity; PPAR delta; PPAR-beta; Reactive Oxygen Species; Sulfones; Thiazoles; Thiophenes; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Vasodilation

2015
Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice.
    Journal of lipid research, 2014, Volume: 55, Issue:7

    Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, FA elongase 5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic TGs and endoplasmic reticulum stress markers (X-box binding protein 1 and cAMP-dependent transcription factor 6α) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for β-oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identification 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fibroblast growth factor 21), but not other cytochrome P450 4A10 (CYP4A10), PPAR-target genes. FA products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPARβ-dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPARβ agonist (GW0742) decreased (14)C-18:2,n-6 in TGs but did not affect β-oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPARβ activity, ATGL expression, and TG catabolism, but not FA oxidation.

    Topics: Acetyltransferases; Animals; Endoplasmic Reticulum Stress; Fatty Acid Elongases; Hep G2 Cells; Hepatocytes; Humans; Lipase; Liver; Male; Mice; Obesity; PPAR-beta; Thiazoles; Triglycerides

2014
Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents.
    Journal of medicinal chemistry, 2011, Feb-10, Volume: 54, Issue:3

    Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.

    Topics: Administration, Oral; Animals; Binding, Competitive; Biological Availability; Crystallography, X-Ray; Diabetes Mellitus; Dogs; ERRalpha Estrogen-Related Receptor; Ethers; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Ligands; Macaca fascicularis; Male; Mice; Mice, Knockout; Models, Molecular; Molecular Structure; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Structure-Activity Relationship; Thiazolidinediones; Triglycerides

2011
Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice.
    Hepatology (Baltimore, Md.), 2008, Volume: 48, Issue:2

    Primary nonalcoholic fatty liver disease is one of the most common forms of chronic liver diseases and is associated with insulin-resistant states such as diabetes and obesity. Recent work has revealed potential implications of peroxisome proliferator-activated receptor-delta (PPARdelta) in lipid homeostasis and insulin resistance. In this study, we examined the effect of PPARdelta on sterol regulatory element-binding protein-1 (SREBP-1), a pivotal transcription factor controlling lipogenesis in hepatocytes. Treatment with GW0742, the PPARdelta agonist, or overexpression of PPARdelta markedly reduced intracellular lipid accumulation. GW0742 and PPARdelta overexpression in hepatocytes induced the expression of insulin-induced gene-1 (Insig-1), an endoplasmic reticulum protein braking SREBP activation, at both the mRNA and the protein levels. PPARdelta inhibited the proteolytic processing of SREBP-1 into the mature active form, thereby suppressing the expression of the lipogenic genes fatty acid synthase, stearyl CoA desaturase-1, and acetyl coenzyme A carboxylase. Our results revealed a direct binding of PPARdelta to a noncanonical peroxisome proliferator responsive element motif upstream of the transcription initiation site of human Insig-1. The disruption of this site diminished the induction of Insig-1, which suggested that Insig-1 is a direct PPARdelta target gene in hepatocytes. Knockdown of endogenous Insig-1 attenuated the suppressive effect of GW0742 on SREBP-1 and its target genes, indicating PPARdelta inhibited SREBP-1 activation via induction of Insig-1. Furthermore, overexpression of PPARdelta by intravenous infection with the PPARdelta adenovirus induced the expression of Insig-1, suppressed SREBP-1 activation, and, consequently, ameliorated hepatic steatosis in obese db/db mice.. Our study reveals a novel mechanism by which PPARdelta regulates lipogenesis, suggesting potential therapeutic applications of PPARdelta modulators in obesity and type 2 diabetes, as well as related steatotic liver diseases.

    Topics: Animals; Cell Line, Tumor; Diabetes Complications; Diabetes Mellitus; Hepatocytes; Humans; Lipogenesis; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peroxisome Proliferators; PPAR delta; Response Elements; RNA, Small Interfering; Sterol Regulatory Element Binding Protein 1; Thiazoles; Transfection

2008