Abstract 22: Ablation of Leptin Receptors in the Brain Subfornical Organ Attenuates Leptin-induced Increases in Renal Sympathetic Nerve Activity (RSNA) But Spares Its Effect on Food Intake and Body Weight

Abstract

The adipocyte-derived hormone leptin acts within the central nervous system to decrease food intake and body weight and to increase sympathetic nerve activity to the kidney. Although most studies have focused on hypothalamic brain regions, recent findings have identified the long form of the leptin receptor (ObR) in the circumventricular subfornical organ (SFO), a forebrain region devoid of a blood-brain barrier. Here we tested the hypothesis that ObR receptors in the SFO are functionally involved in the decreases in food intake and body weight and increases in RSNA due to leptin. To delete ObR receptors selectively in the SFO, an adenovirus encoding Cre-recombinase (Cre; n=4) was targeted to this brain region in ObR flox mice. LacZ served as a control (n=4). After 7 days, systemic leptin (i.p. 30μg bi-daily) was administered over 3 days. Leptin caused a significant decrease in body weight and food intake in control animals. Interestingly, ablation of the ObR receptor in the SFO did not attenuate the leptin-induced decreases in either body weight (peak decrease: Δ-2.2±0.1 vs. Δ-2.4±0.2 g; LacZ vs. Cre, p>0.05) or food intake. Similar findings were obtained with daily intracerebroventricular (ICV) administration of leptin. To examine a role for SFO-ObR in cardiovascular-sympathetic regulation, ObR flox mice underwent SFO-targeted adenoviral delivery of Cre or LacZ as above. Following recovery, mice were instrumented for anesthetized recordings of RSNA and leptin was administered systemically (i.v. 120μg) or ICV (2μg). Both systemic and centrally administered leptin caused robust increases in RSNA over 4 hours in control mice. This response was completely abolished in mice with SFO-targeted deletion of ObR (e.g., i.v. leptin % RSNA 4hr: 116±16 vs. -20±9 v*s/min; LacZ vs. Cre, p<0.05, n=5/group). These findings suggest that ObR receptors in the SFO play a critical role in leptin-induced renal sympathoexcitation, but not in the body weight and food intake effects of leptin. These findings emphasize two important concepts: 1) A distributed brain network as opposed to a hypothalamic-centric concept of leptin action; and 2) Selectivity of leptin action mediated by distinct brain regions, including the circumventricular organs. HL063887, HL084207