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Pharmacol Res. 2016 May;107:125-136. doi: 10.1016/j.phrs.2016.02.027. Epub 2016 Mar 11.

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.

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National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy.
National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy; Department of Biological and Environmental Science and Technology (DISTEBA), University of Salento, Lecce, Italy.
Division of Pediatric Endocrinology, Diabetes and Obesity, Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany.
Department of Biological and Environmental Science and Technology (DISTEBA), University of Salento, Lecce, Italy.
Roche Pharmaceuticals, Basel, Switzerland.
⿿G. d⿿Annunzio⿿ University and Center of Excellence on Aging, Chieti, Italy; ⿿G. Monasterio⿿ Foundation for Clinical Research, Pisa, Italy. Electronic address:


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.


Adipocytes; Inflammation; Metabolic syndrome; Obesity; PPARs; Peroxisome proliferator activated receptors; Type 2 diabetes

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