Abstract 221: Sympathetic and Metabolic Consequences of Deleting the Insulin Receptor from Proopiomelanocortin Neurons

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Hypothalamic insulin receptor (IR) signaling has been implicated in the regulation of energy homeostasis and sympathetic nerve activity (SNA). Recent studies demonstrated that the sympathetic action of insulin emanates from the hypothalamic arcuate nucleus (ARC). However, the specific neuronal population within the ARC that mediates the sympathetic effect of insulin is unknown. We hypothesized that proopiomelanocortin (POMC) neurons of the ARC which contain the insulin receptor (IR) are critical for the increases in SNA in response to insulin. To test this, we generated mice lacking the IR specifically in POMC neurons (IRΔPOMC mice) by crossing the IRflox/flox mice with POMCCre mice. First, we visualized POMC promoter-driven Cre recombinase expression by crossing POMCCre mice with tdTomato reporter mice. tdTomato fluorescence was detected mainly in the ARC and overlapped with staining for β-endorphin (a POMC proteolytic product). As previously reported, body weight of IRΔPOMC mice (at 12 weeks of age: 23±1 g, n=8) was not significantly different (p=0.21) from littermate controls (25±2 g, n=8). There was also no significant difference in fat pad weights (brown adipose tissue, peri-gonadal and peri-renal) between IRΔPOMC mice and littermate controls. Next, we used direct multifiber nerve recording to assess the sympathetic effects of insulin. In wild type mice, intracerebroventricular (ICV) administration of insulin (100 μU) caused a robust increase in lumbar SNA (202±36%, n=7). Surprisingly, genetic deletion of the IR from POMC neurons by loxP-Cre recombination did not alter the sympathetic response as indicated by the comparable (p=0.24 vs. littermate controls) increase in lumbar SNA in the IRΔPOMC mice in response to ICV insulin (264±40%, n=7). Ongoing studies are aimed to determine whether deletion of the IR from POMC neurons interferes with the ability of insulin to increase SNA subserving tissues other than the hindlimb. We conclude that insulin receptor signaling in POMC neurons does not mediate the lumbar sympathetic nerve activation evoked by insulin.

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