title: Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes.
abstract: Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)α and γ, combining in a single molecule the metabolic and inflammatory-regulatory properties of α and γ agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPARα/γ agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPARα or γ fenofibrate or rosiglitazone, respectively, for 24h before stimulation with TNF-α. Aleglitazar, at concentrations as low as 10nmol/L, providing the half-maximal transcriptional activation of both PPARα and PPARγ, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-α-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-α-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPARα and γ agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPARα and γ agonism, but with no evidence of synergism.
authors.affiliation: National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Massaro
authors.affiliation: National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy.
authors.forename: Egeria
authors.initials: E
authors.lastname: Scoditti
authors.affiliation: National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy; Department of Biological and Environmental Science and Technology (DISTEBA), University of Salento, Lecce, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy.
authors.forename: Maria Annunziata
authors.initials: MA
authors.lastname: Carluccio
authors.affiliation: National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Calabriso
authors.affiliation: Division of Pediatric Endocrinology, Diabetes and Obesity, Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.affiliation: Department of Biological and Environmental Science and Technology (DISTEBA), University of Salento, Lecce, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Storelli
authors.affiliation: Roche Pharmaceuticals, Basel, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wright
authors.affiliation: ⿿G. d⿿Annunzio⿿ University and Center of Excellence on Aging, Chieti, Italy; ⿿G. Monasterio⿿ Foundation for Clinical Research, Pisa, Italy. Electronic address: rdecater@unich.it.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D052242:Adiponectin / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D054357:Chemokine CXCL10 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D013876:Thiophenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D007004:Hypoglycemic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C542437:aleglitazar; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Adipocytes; Inflammation; Metabolic syndrome; Obesity; PPARs; Peroxisome proliferator activated receptors; Type 2 diabetes