Abstract P249: ICV Infusion Of AgRP Modulates Feeding Behavior And Energy Expenditure In Mice

Abstract

A subset of Agouti-related protein (AgRP) neurons within the arcuate nucleus express angiotensin type 1a receptors (AT1A), and genetic ablation of AT1A in these cells disinhibits AgRP gene expression and attenuates energy expenditure (EE) in mice. To further understand the role of AgRP in metabolic control, and to establish relevant dosing schedules in this species, here we tested the effect of intracerebroventricular infusion (icv) of recombinant AgRP on metabolic functions in C57BL/6J male mice. First, we examined the effects of AgRP(82-132) (21 days, 1 or 10 nmol/d, icv) or artificial cerebrospinal fluid (aCSF) using metabolic cages. High dose AgRP reduced body mass (aCSF n=12, +0.8±0.6 vs 1 nmol/d n=14, +0.6±0.6 vs 10 nmol/d n=11, -1.5±0.5 p<0.05 g/21d), without affecting food intake (15.1±1.2 vs 14.1±1.1 vs 16.3±1.1 kcal/d) or digestive efficiency (85.2±0.5 vs 84.5±0.7 vs 85.1±0.6 %), but a significant reduction in energy efficiency (+3.8±2.0 vs +2.7±2.8 vs -5.9±2.2 p<0.05 mg/kcal) indicated increased total EE. Next, we examined the effect of AgRP(82-132) (14 days, 1 nmol/d, icv) using a multiplexed system (Promethion, Sable). AgRP had no effect on body mass (25.1±1.2, n=8 vs 26.7±0.5, n=8), overall body composition (by NMR), heat production (Weir, 24h: 0.485±0.015 vs 0.490±0.022 kcal/h), or respiratory exchange ratio (0.88±0.01 vs 0.89±0.01). AgRP increased total food intake (10.1±0.6, n=8 vs 11.9±0.5, n=8, kcal/d, p=0.03) through a synergistic effect on number of meals and median meal mass. We conclude that AgRP (1-10 nmol/d, 2-3 wk, icv) infusion causes subtle changes in feeding behavior without effect on digestive efficiency. In contrast, EE is paradoxically increased by AgRP when infused at a high dose (10 nmol/d). We postulate that these differences may reflect differential accessibility of the peptide to relevant feeding vs autonomic control regions of the hypothalamus when infused into the cerebral ventricles, and/or compensatory increases in EE secondary to changes in feeding behavior. Future studies to deconvolute the role of AgRP in the control of EE in mice will require site-specific delivery of the peptide to relevant target regions or manipulation of its receptor in those regions. Funding: HL134850, HL084207