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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.

Author information

1
National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy.
2
National Research Council (CNR) Institute of Clinical Physiology, Lecce, Italy; Department of Biological and Environmental Science and Technology (DISTEBA), University of Salento, Lecce, Italy.
3
Division of Pediatric Endocrinology, Diabetes and Obesity, Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany.
4
Department of Biological and Environmental Science and Technology (DISTEBA), University of Salento, Lecce, Italy.
5
Roche Pharmaceuticals, Basel, Switzerland.
6
⿿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.

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.

KEYWORDS:

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

PMID:
26976796
DOI:
10.1016/j.phrs.2016.02.027
[Indexed for MEDLINE]

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