Increased Energy expenditure induced by Ptp1b deletion in proopiomelanocortin (POMC) neurons leads to inflammation and endothelial dysfunction

Abstract

Increased energy expenditure is associated with inflammation while genetic deletion of cytokine sensitizes mice to obesity. Deletion of Protein tyrosine phosphatase 1b (Ptp1b), a negative regulator of leptin and insulin signaling pathways, in proopiomelanocotin neurons protects mice from obesity and type 2 diabetes by increasing energy expenditure. However whether the deletion of POMC‐Ptp1b induces inflammation and impairs the cardiovascular function is unknown. We analyzed the metabolic and endothelial function of wild‐type (WT) and POMC‐Ptp1b KO mice (KO). Total body fat was reduced in KO animals as measured by EchoMRI and fat pad measurements. Plasma TNF‐α levels were doubled KO vs WT mice. Measurement of aortic rings endothelial function revealed that POMC‐Ptp1b deletion reduced ACh‐induced relaxation. Pre‐incubation with tempol [superoxide dismutase mimetic (SOD)], catalase and GKT137831 (Nox1‐4 inhibitor) restored endothelial function in KO mice. Moreover, quantitative real time RT‐PCR revealed an increase in NOXA1 and Nox4 expression and a decrease in SOD1‐3 and catalase. Pre‐incubation with indomethacin (COXs inhibitor), NS‐398 (COX2 inhibitor) and SQ28668 (TXA2 receptor antagonist) reverted the impaired relaxation for ACh in aortic rings from KO mice. POMC‐Ptp1b deletion did not affect COX1 expression, but increased COX‐2 gene and protein expression in aorta, as measured by qRT‐PCR and Western Blot respectively. These data suggest that increased energy expenditure induced by POMC‐Ptp1b deletion leads to inflammation triggering an endothelial dysfunction dependent of COX2‐derived products and NADPH‐oxidase generated ROS.