The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis.
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.
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Aykut
A
Üner
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Gabriel H M
GH
Gonçalves
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Wenjing
W
Li
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Matheus
M
Porceban
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Nicole
N
Caron
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Milena
M
Schönke
Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Eric
E
Delpire
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Kenji
K
Sakimura
Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Christian
C
Bjørbæk
AAC, area above the curve; AMPARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; ANCOVA, analysis of covariance; ANOVA, analysis of variance; AUC, area under the curve; AgRP; AgRP, agouti-related peptide; CNS, central nervous system; DAB, 3,3′-diaminobenzidine; DIO, diet-induced obesity; DREADD, Designer Receptor Exclusively Activated by Dedigner Drugs; EPSCs, excitatory post-synaptic synaptic currents; GABA, gamma-aminobutyric acid; GTT, glucose tolerance test; GluN2B; Glycemia; HFD, high-fat diet; HSD, honestly significant difference; ITT, insulin tolerance test; KO, knockout; LTD, long-term depression; LTP, long-term potentiation; Lepob/ob mice, obese leptin-deficient mice; Leptin; Metabolism; NMDAR; NMDARs, N-methyl-d-aspartate receptors; PBS, phosphate-buffered saline; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; RT, room temperature; hrGFP, humanized renilla GFP