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

Abstract

Rationale The hypothalamic arcuate nucleus (ARC) is considered as 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 ObRflox/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 if 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 ObRflox/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.

Sleeve Gastrectomy Reduces Blood Pressure in Obese (fa/fa) Zucker Rats

“…Data are the mean±SEM. Intra-group statistical differences were analyzed by the Kruskal-Wallis test followed by Mann-Whitney's U test; *P<0.05 vs. control group; † †P<0.01 vs. pair-fed group to blood pressure homeostasis inducing a pressor response attributable to central sympathoactivation [23] and a depressor response attributable to the vasodilation of conduit and resistance vessels [24]. Due to the leptin receptor missense mutation, obese (fa/fa) Zucker rats showed an impairment of sympathetic baroreceptor reflexes as well as an impaired vasodilatory response due to a defective intracellular Ca 2+ handling and proliferation in vascular smooth muscle cells, leading to the adult-onset hypertension [25][26][27][28].…”

Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

“…This notion is partly based on work showing that reactivation of MC4R in the SNS, but not the parasympathetic nervous system (PNS), of an otherwise MC4R-null mouse ameliorates hepatic insulin resistance. Numerous other reports also show that leptin acts in the brain to regulate the SNS (9,(51)(52)(53). However, other studies show that leptin acts via the PNS to mediate its beneficial effects (6,36,54).…”

Adipose tissue in control of metabolism

“…In addition, several circulating factors such as insulin, leptin and GLP-1 have been identified to promote thermogenesis through targeting hypothalamus neurons and regulating activity of SNS (Shimizu et al 1987, Rahmouni & Morgan 2007, Sanchez-Alavez et al 2010, Harlan et al 2011, Lockie et al 2012, Beiroa et al 2014, Dodd et al 2015 (Fig. 3).…”