Viral Mediated Neuropeptide Y Expression In The Rat Paraventricular Nucleus Results In Obesity

Viral Mediated Neuropeptide Y Expression in the Rat Paraventricular Nucleus Results in Obesity
Birgitte Tiesjema,* Susanne E. la Fleur,* Mieneke C. M. Luijendijk,* Maike A. D. Brans,* En-Ju D. Lin,† Matthew J. During,† and Roger A. Adan*

Abstract TIESJEMA, BIRGITTE, SUSANNE E. LA FLEUR, MIENEKE C. M. LUIJENDIJK, MAIKE A. D. BRANS, EN-JU D. LIN, MATTHEW J. DURING, AND ROGER A. ADAN. Viralmediated neuropeptide Y expression in the rat paraventricular nucleus results in obesity. Obesity. 2007;15: 2424 –2435. Objective: Chronic central administration of neuropeptide Y (NPY) has dramatic effects on energy balance; however, the exact role of the hypothalamic paraventricular nucleus (PVN) in this is unknown. The aim of this study was to further unravel the contribution of NPY signaling inthe PVN to energy balance. Research Methods and Procedures: Recombinant adenoassociated viral particles containing NPY (rAAV-NPY) were injected in the rat brain with coordinates targeted at the PVN. For three weeks, body weight, food intake, endocrine parameters, body temperature, and locomotor activity were measured. Furthermore, effects on insulin sensitivity and expression of NPY, agouti-relatedprotein (AgRP), and pro-opiomelanocortin in the arcuate nucleus were studied. Results: Food intake was increased specifically in the light period, and dark phase body temperature and locomotor activity were reduced. This resulted in obesity characterized by increased fat mass; elevated plasma insulin, leptin, and

adiponectin; decreased AgRP expression in the arcuate nucleus; and decreasedinsulin sensitivity; whereas plasma corticosterone was unaffected. Discussion: These data suggest that increased NPY expression targeted at the PVN is sufficient to induce obesity. Interestingly, plasma concentrations of leptin and insulin were elevated before a rise in food intake, which suggests that NPY in the PVN influences leptin and insulin secretion independently from food intake. Thisstrengthens the role of the PVN in regulation of energy balance by NPY. Key words: central feeding regulation, animal models, neuropeptide Y, hypothalamus

Received for review September 5, 2006. Accepted in final form March 1, 2007. The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordancewith 18 U.S.C. Section 1734 solely to indicate this fact. *Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands; and †Department of Molecular Medicine and Pathology, University of Auckland School of Medicine, Auckland, New Zealand. Address correspondence to Roger A. H. Adan, Rudolf Magnus Institute ofNeuroscience, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. E-mail: r.a.h.adan@umcutrecht.nl Copyright © 2007 NAASO

Neuropeptide Y (NPY),1 which is widely distributed throughout the brain, has a robust feeding effect when injected centrally (1,2). Moreover, it decreases metabolic rate and thermogenesis (3–5). One week of chronic intracerebroventricular (ICV) administration of NPY resultsin an obese phenotype characterized by hyperphagia; elevated plasma concentrations of corticosterone, leptin, and insulin; and increased lipogenesis in liver and adipose tissue (6 –10). Neurons in the arcuate nucleus that express NPY have been implicated in the regulation of energy balance and project to a variety of hypothalamic nuclei, including the paraventricular (PVN), dorsomedial and lateralhypothalamic nuclei, and the medial pre-optic area (11–14). Although all these nuclei may be involved in this regulation, acute injections of NPY in the PVN and the perifornical

Introduction

1 Nonstandard abbreviations: NPY, neuropeptide Y; ICV, intracerebroventricular; PVN, paraventricular nucleus; AgRP, agouti-related protein; rAAV, recombinant adeno-associated viral particles; NSE,...