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

Christian Bjørbæk,Aykut Üner,Wenjing Li,Gabriel H.M. Gonçalves,Nicole Caron,Kenji Sakimura,Matheus Porceban,Milena Schönke,Eric Delpire

doi:10.1016/j.molmet.2015.06.010

Abstract

ObjectiveHypothalamic 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.MethodsWe 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.ResultsWe 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 Lepob/ob mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lepob/ob mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions.ConclusionsGluN2B-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.

Highlights

Hypothalamic agouti related peptide (AgRP) and proopiomelanocortin (POMC) producing neurons play important roles in the regulation of body weight homeostasis
We here examined whether GluN2A and GluN2B subunits in AgRP and POMC neurons are important for energy homeostasis control
GluN2B deletion in POMC neurons did not affect body weight, food intake, body composition or leptin levels (Figure 2AeD). These results suggest that n-methyl-D-aspartate receptors (NMDARs) GluN2B subunits in AgRP neurons are required for normal regulation of body weight homeostasis

Summary

Introduction

Hypothalamic agouti related peptide (AgRP) and proopiomelanocortin (POMC) producing neurons play important roles in the regulation of body weight homeostasis. Activation of AgRP neurons in mice promotes a state of positive energy balance by increasing energy intake and decreasing energy expenditure, while stimulation of POMC neurons promote a state of negative energy balance [1e6]. Arcuate nucleus (ARC) AgRP and POMC neurons are regulated by neuronal synaptic inputs, circulating metabolites and peripheral hormonal signals such as leptin, insulin and ghrelin. Both groups of cells have the capacity to mediate potent anti-diabetic actions by leptin [7e9].

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Conclusion