PTEN downregulation in adipocytes promotes inflammation of adipose tissue

Background and aims: The phosphoinositide phosphatase PTEN is a potent tumor suppressor and a regulator of insulin sensitivity in peripheral tissues. In adipocytes, experimental alterations of PTEN expression modulate the sensitivity of these cells to insulin. However, virtually nothing is known about the pathophysiological regulation of endogenous PTEN in adipose tissue. Herein, we investigated in vivo and in vitro whether alterations of PTEN expression in adipocytes are associated with the metabolic syndrome and what are the functional outcomes of dysregulated PTEN expression/activity. Materials and methods: PTEN expression was examined in vivo in adipose tissue of rats and human with the metabolic syndrome. Metabolic factors mediating dysregulation of PTEN expression in adipocytes and the subsequent effects on the physiology of these cells were investigated in vitro using human CHUB-S7 preadipocytes. Results: We demonstrated that PTEN is downregulated, both at the mRNA and protein levels, in adipose tissue of diabetic/obese ZDF rats and in subcutaneous adipose tissue of obese human patients. PTEN downregulation correlated with degradation of IκBα and hyperactivation of NF-κB, a transcription factor previously described to modulate PTEN expression. The expression of SHIP2, another PtdIns(3,4,5)P3 phosphatase involved in the control of insulin sensitivity and the development of obesity, was not altered. In vitro analyses using differentiated human CHUB-S7 preadipocytes showed that PTEN downregulation is not triggered by high concentrations of glucose or fatty acids. In contrast, the pro-inflammatory cytokines IL-1α and TNFα, significantly downregulate PTEN expression. Consistent with the IL1α-dependent PTEN downregulation, long-term incubation of CHUB-S7 cells with IL-1α potentiates insulin-induced Akt and ERK1/2 signaling. We finally showed that PTEN downregulation in CHUB-S7 preadipocytes by PTEN siRNAs induced an increased secretion of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα. Conclusion: Taken together, these data indicate that PTEN expression is downregulated in adipose tissue of obese/diabetic subjects, potentially via cytokine- mediated activation of the NF-κB pathway. PTEN downregulation in adipocytes might in turn worsen adipose tissue inflammation through a vicious circle by further stimulating the secretion of pro-inflammatory cytokines