Beneficial effects of PTP1B deficiency on brown adipocyte differentiation and protection against apoptosis induced by pro- and anti-inflammatory stimuli

Insulin is an inducer of brown fat adipogenesis through the activation of a signalling network that involves positive/negative modulators. Given the importance of brown adipose tissue (BAT) for basal thermogenic energy expenditure, we investigated the role of PTP1B in the acquisition of terminal differentiated phenotype and in the apoptotic responses of brown adipocytes. Immortalized brown preadipocytes lacking (PTP1B-/-) or expressing (PTP1B+/+) PTP1B have been generated. PTP1B deficiency accelerated a full program of brown adipogenesis including induction of transcription factors, coactivators, adipogenic markers and signalling molecules. Fully differentiated PTP1B-/- brown adipocytes were resistant to tumor necrosis factor (TNFα)-induced apoptosis as these cells were protected against caspase-8 activation, FLIP degradation, Bid cleavage and caspase-3 activation compared to wild-type controls. These events were recovered by PTP1B rescue. Survival signalling including phosphorylation of IRS-1 and Akt/PKB and BclxL expression were decreased in TNFα-treated PTP1B-/- cells but not in the wild-type. Similarly, PTP1B-/- brown adipocytes were protected against resveratrol-induced apoptosis. Phosphorylation of Akt/PKB and Foxo1 phosphorylation/acetylation decreased exclusively in resveratrol-treated wild-type cells, leading to nuclear localization of Foxo1 and up-regulation of Bim. Thus, PTP1B inhibition could be of benefit against obesity by counteracting TNFα-induced brown fat atrophy, and combined with resveratrol might improve low-grade inflammation. © 2009 Elsevier Inc. All rights reserved.This work was supported by grants SAF2009-08114 and CIT-090100-2007-35 (MCINN, Spain), and by the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto Carlos III, MCINN, (Spain).Peer Reviewe