Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin

Abstract

Purpose of review: Here, we review the current understanding of the functional neuroanatomy of neurons expressing Agouti-related peptide (AgRP) and the angiotensin 1A receptor (AT_1A) within the arcuate nucleus (ARC) in the control of energy balance.

Recent findings: The development and maintenance of obesity involves suppression of resting metabolic rate (RMR). RMR control is integrated via AgRP and proopiomelanocortin neurons within the ARC. Their projections to other hypothalamic and extrahypothalamic nuclei contribute to RMR control, though relatively little is known about the contributions of individual projections and the neurotransmitters involved. Recent studies highlight a role for AT_1A, localized to AgRP neurons, but the specific function of AT_1A within these cells remains unclear. AT_1A functions within AgRP neurons to control RMR, but additional work is required to clarify its role within subpopulations of AgRP neurons projecting to distinct second-order nuclei, and the molecular mediators of its signaling within these cells.

Keywords: Agouti-related peptide; Bioenergetics; Leptin; Metabolism; Obesity; Renin-angiotensin system.

Figure 1. Angiotensin AT_1A localization to AgRP neurons: molecular consequences, and projections that may mediate RMR control

(A) Fluorescent in situ hybridization, demonstrating localization of AT_1A to a subset of neurons expressing AgRP within the ARC ([15], with permission from J Clin Invest). White arrows identify cells which express AgRP and AT_1A, whereas black arrows identify cells which express AgRP but not AT_1A. (B) Expression of GAD65, GAD67, VGAT, AgRP and NPY in mice with genetic disruption of AT_1A specifically within cells that express AgRP (AT_1A^AgRP-KO) ([15], with permission, and unpublished). (C) Schematic representation of the effects of angiotensin II signaling via AT_1A in AgRP neurons in the arcuate nucleus. GAD glutamic acid decarboxylase; VGAT vesicular GABA transporter; ARC arcuate nucleus; ANG angiotensin II. (D) Control of resting energy expenditure by ARC AgRP neurons: neurocircuitry and neurotransmitters involved. Question marks indicate putative neurotransmitters. ARC arcuate nucleus; PVN paraventricular nucleus; DMH dorsomedial hypothalamus; VMH ventromedial hypothalamus; LHA lateral hypothalamus; MCH melanin-concentrating hormone; POA preoptic area; NTS nucleus tractus solitarius; Y1 NPY receptor 1; MC4R melanocortin 4 receptor; AT_1A angiotensin receptor 1A; SNA sympathetic nervous activity; BAT brown adipose tissue.