NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice

PLOS ONE, Jun 2010

Background Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. Methodology/Principal Findings We thus generated two conditional knockout mouse models, Y2lox/lox and NPYCre/+;Y2lox/lox, in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPY-producing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver cartinine palmitoyltransferase (CPT1) and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC). While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons. Conclusions/Significance Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus, reducing lipogenic pathways in liver and/or skeletal muscle in females. These data also reveal as an anti-osteogenic effect of Y2 receptors on hypothalamic NPY-expressing neurons on trabecular but not on cortical bone.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0011361&type=printable

NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice

et al. (2010) NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice. PLoS ONE 5(6): e11361. doi:10.1371/journal.pone.0011361 NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice Yan-Chuan Shi 0 Shu Lin 0 Iris P. L. Wong 0 Paul A. Baldock 0 Aygul Aljanova 0 Ronaldo F. Enriquez 0 Lesley Castillo 0 Natalie F. Mitchell 0 Ji-Ming Ye 0 Lei Zhang 0 Laurence Macia 0 Ernie Yulyaningsih 0 Amy D. Nguyen 0 Sabrina J. Riepler 0 Herbert Herzog 0 Amanda Sainsbury 0 Frederic Andre Meunier, The University of Queensland, Australia 0 1 Neuroscience Research Program, Garvan Institute of Medical Research , Sydney, New South Wales , Australia , 2 Diabetes and Obesity Research Program, Garvan Institute of Medical Research , Sydney, New South Wales , Australia , 3 Faculty of Medicine, University of New South Wales , Sydney, New South Wales , Australia , 4 School of Medical Sciences, University of New South Wales , Sydney, New South Wales , Australia Background: Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPYexpressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. Methodology/Principal Findings: We thus generated two conditional knockout mouse models, Y2lox/lox and NPYCre/ +;Y2lox/lox, in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPYproducing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver cartinine palmitoyltransferase (CPT1) and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC). While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons. Conclusions/Significance: Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus, reducing lipogenic pathways in liver and/or skeletal muscle in females. These data also reveal as an anti-osteogenic effect of Y2 receptors on hypothalamic NPY-expressing neurons on trabecular but not on cortical bone. - Funding: This research was supported by the National Health and Medical Research Council (NHMRC) of Australia grants # 427661 & #427606, and AS, HH and PB are supported by NHMRC Fellowships (http://www.nhmrc.gov.au/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Neuropeptide Y (NPY), a 36-amino acid peptide, is widely expressed in the central and peripheral nervous systems and is an important regulator of numerous physiological processes, including energy balance [1,2]. In the central nervous system, NPY is present in regions such as the hypothalamus, cerebral cortex, brain stem, striatum and limbic structures [3], with the highest expression in the hypothalamic arcuate nucleus (Arc) [4]. Central control of energy balance is predominantly a function of hypothalamic pathways including key connections with the Arc. The Arc is located at the base of hypothalamus, and has direct access to circulating hormones due to a semi-permeable blood brain barrier [5]. Therefore, neurons within the Arc are able to respond rapidly to peripheral signals and then project broadly to other brain regions to modulate energy balance [6]. Located within the Arc are two major populations of neurons that are known to regulate energy balance: orexigenic NPY/agouti-related protein (AGRP) neurons and anorexigenic pro-opiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) neurons [7]. Activation of NPY/AGRP neurons leads to release of NPY and AGRP, which stimulate appetite, (...truncated)


This is a preview of a remote PDF: http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0011361&type=printable

Yan-Chuan Shi, Shu Lin, Iris P. L. Wong, Paul A. Baldock, Aygul Aljanova, Ronaldo F. Enriquez, Lesley Castillo, Natalie F. Mitchell, Ji-Ming Ye, Lei Zhang, Laurence Macia, Ernie Yulyaningsih, Amy D. Nguyen, Sabrina J. Riepler, Herbert Herzog, Amanda Sainsbury. NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice, PLOS ONE, 2010, Volume 5, Issue 6, DOI: 10.1371/journal.pone.0011361