Enhanced leptin‐TRPC signaling in the hypothalamus contributes to the exaggerated sympatho‐excitation in type 2 diabetic rats (1130.9)

Abstract

Accumulated evidence indicates that type 2 diabetes (T2D) is associated with enhanced sympathetic activation. Transient receptor potential canonical channels (TRPC) have been found in pro‐opiomelanocortin neurons and activated by leptin. The present study was conducted to investigate the role for leptin‐TRPC signaling in centrally mediated sympathetic response in rats with T2D. In high‐fat diet and low‐dose strepzotocin (30mg/kg)‐induced T2D rats, mRNA levels of TRPC subtype including TRPC1, 4, 5 and 6 were significantly increased in the paraventricular nucleus (PVN) and arcuate nucleus (ARCN) compared to control rats (n=8/group). Whole‐cell patch‐clamp was conducted in primary cultured hypothalamic neurons to record TPPC currents. Neurons from T2D rats had significant increased TRPC currents (about 2 folds to the control). In anaesthetized condition, microinjections of leptin (5ng~100ng) into the ARCN and PVN induced increases in renal sympathetic nerve activity and blood pressure. These effects were significantly blocked by pre‐microinjections of TRPC inhibitors (2APB and SKF96365). In cultured neuronal cell NG108, pre‐incubation with leptin (0.625~2.5μM) for 24hrs induced significant increases of TRPC mRNA expressions (TRPC1, 4 and 5). Taken together, these data suggest that within the hypothalamic nuclei, leptin‐induced sympatho‐excitation in T2D maybe mediated through an activation of TRPC. Supported by NIH grant DK82956.Grant Funding Source: NIH DK82956