The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis

被引：23

作者：

Uner, Aykut ^{[1
,2
,5
]}

Goncalves, Gabriel H. M. ^{[1
,2
]}

Li, Wenjing ^{[1
,2
]}

Porceban, Matheus ^{[1
,2
]}

Caron, Nicole ^{[1
,2
]}

Schonke, Milena ^{[1
,2
]}

Delpire, Eric ^{[3
]}

Sakimura, Kenji ^{[4
]}

Bjorbaek, Christian ^{[1
,2
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol & Metab, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Boston, MA 02215 USA

[3] Vanderbilt Univ, Dept Anesthesiol, Sch Med, Nashville, TN 37232 USA

[4] Niigata Univ, Brain Res Inst, Dept Cellular Neurobiol, Niigata 9518585, Japan

[5] Adnan Menderes Univ, Dept Physiol, Fac Vet Med, TR-09016 Aydin, Turkey

来源：

MOLECULAR METABOLISM | 2015年 / 4卷 / 10期

关键词：

AgRP; NMDAR; GluN2B; Metabolism; Glycemia; Leptin; HIPPOCAMPAL SYNAPTIC PLASTICITY; ARCUATE NUCLEUS; ENERGY-BALANCE; PROOPIOMELANOCORTIN NEURONS; LOCOMOTOR-ACTIVITY; GENE-EXPRESSION; MUTANT MICE; LEPTIN; MELANOCORTIN; OBESITY;

D O I：

10.1016/j.molmet.2015.06.010

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective: Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-D-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. Methods: We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. Results: We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep(ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep(ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions. Conclusions: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action. (C) 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

引用

页码：678 / 691

页数：14