Ablation of the Leptin Receptor in the Hypothalamic Arcuate Nucleus Abrogates Leptin-Induced Sympathetic Activation

Abstract

Rationale: The hypothalamic arcuate nucleus (ARC) is considered a major site for leptin signaling that regulates several physiological processes. Objective: To test the hypothesis that leptin receptor in the ARC is required to mediate leptin-induced sympathetic activation. Methods and Results: First, we used the ROSA Cre-reporter mice to establish the feasibility of driving Cre expression in the ARC in a controlled manner with bilateral microinjection of adenovirus-expressing Cre-recombinase (Ad-Cre). Ad-Cre microinjection into the ARC of ObR flox/flox mice robustly reduced ObR expression and leptin-induced Stat3 activation in the ARC but not in the adjacent nuclei, confirming the efficacy and selectivity of the ARC deletion of ObR. Critically, deletion of ObR in the ARC attenuated brown adipose tissue and renal sympathetic nerve responses to leptin. We also examined whether ObR in the ARC is required for the preserved leptin-induced increase in renal sympathetic activity in dietary obesity. We found that deletion of ARC ObR abrogated leptin-induced increases in renal sympathetic discharge and resolved arterial pressure elevation in diet-induced obese ObR flox/flox mice. Conclusions: These data demonstrate a critical role for ObR in the ARC in mediating the sympathetic nerve responses to leptin and in the adverse sympathoexcitatory effects of leptin in obesity.