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

Üner A, Gonçalves GH, Li W, Porceban M, Caron N, Schönke M, Delpire E, Sakimura K, Bjørbæk C - Mol Metab (2015)

Bottom Line: NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function.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.Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Deletion of GluN2B in AgRP and POMC neurons: Blood glucose and insulin, and glucose- and insulin-tolerance. (A–D) Fed blood glucose and insulin levels (15–17 weeks of age) in animals from AgRP (A and C) and POMC (B and D) studies, respectively. (E–H) Glucose tolerance test (GTT) following 15 h food removal (2 mg/g d-glucose, intraperitoneal) and insulin tolerance test (ITT) following 5 h food removal (1.2 U/kg insulin, intraperitoneal) (15–17 weeks of age) of AgRP (E and G) and POMC (F and H) studies, respectively. AgRP and POMC data are from female and male mice, respectively, and are shown as means ± SEM (n = 3–9/group). P > 0.05 for all experiments applying ANCOVA or repeated measures two-way ANCOVA. Logarithmic transformations were done for GTT values of AgRP study and ITT values of POMC study. Controls represent GluN2Bflox/flox mice. NS: Not significant.
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fig5: Deletion of GluN2B in AgRP and POMC neurons: Blood glucose and insulin, and glucose- and insulin-tolerance. (A–D) Fed blood glucose and insulin levels (15–17 weeks of age) in animals from AgRP (A and C) and POMC (B and D) studies, respectively. (E–H) Glucose tolerance test (GTT) following 15 h food removal (2 mg/g d-glucose, intraperitoneal) and insulin tolerance test (ITT) following 5 h food removal (1.2 U/kg insulin, intraperitoneal) (15–17 weeks of age) of AgRP (E and G) and POMC (F and H) studies, respectively. AgRP and POMC data are from female and male mice, respectively, and are shown as means ± SEM (n = 3–9/group). P > 0.05 for all experiments applying ANCOVA or repeated measures two-way ANCOVA. Logarithmic transformations were done for GTT values of AgRP study and ITT values of POMC study. Controls represent GluN2Bflox/flox mice. NS: Not significant.

Mentions: Because AgRP and POMC neurons can respond to glucose and orchestrate blood glucose control [7,13,43,47], we measured fed glucose levels and performed glucose (GTT) and insulin (ITT) tolerance tests in young body-weight matched mice. GluN2B deletion in AgRP and POMC neurons did not affect fed blood glucose or serum insulin levels (Figure 5A–D), GTTs (AUC [AgRP]: 20.2 ± 0.76 × 103 and 24.1 ± 1.48 × 103 AgRP-GluN2B KO vs control, P > 0.05. AUC [POMC]: 31.6 ± 2.63 × 103 and 30.5 ± 1.40 × 103 POMC-GluN2B KO vs control, P > 0.05) (Figure 5E and F) or ITTs (AAC [AgRP]: 9.19 ± 0.97 × 103 and 9.12 ± 0.71 × 103 AgRP-GluN2B KO vs control, P > 0.05. AAC [POMC]: 7.46 ± 0.84 × 103 and 10.8 ± 1.60 × 103 POMC-GluN2B KO vs control, P > 0.05) (Figure 5G and H).


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

Üner A, Gonçalves GH, Li W, Porceban M, Caron N, Schönke M, Delpire E, Sakimura K, Bjørbæk C - Mol Metab (2015)

Deletion of GluN2B in AgRP and POMC neurons: Blood glucose and insulin, and glucose- and insulin-tolerance. (A–D) Fed blood glucose and insulin levels (15–17 weeks of age) in animals from AgRP (A and C) and POMC (B and D) studies, respectively. (E–H) Glucose tolerance test (GTT) following 15 h food removal (2 mg/g d-glucose, intraperitoneal) and insulin tolerance test (ITT) following 5 h food removal (1.2 U/kg insulin, intraperitoneal) (15–17 weeks of age) of AgRP (E and G) and POMC (F and H) studies, respectively. AgRP and POMC data are from female and male mice, respectively, and are shown as means ± SEM (n = 3–9/group). P > 0.05 for all experiments applying ANCOVA or repeated measures two-way ANCOVA. Logarithmic transformations were done for GTT values of AgRP study and ITT values of POMC study. Controls represent GluN2Bflox/flox mice. NS: Not significant.
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fig5: Deletion of GluN2B in AgRP and POMC neurons: Blood glucose and insulin, and glucose- and insulin-tolerance. (A–D) Fed blood glucose and insulin levels (15–17 weeks of age) in animals from AgRP (A and C) and POMC (B and D) studies, respectively. (E–H) Glucose tolerance test (GTT) following 15 h food removal (2 mg/g d-glucose, intraperitoneal) and insulin tolerance test (ITT) following 5 h food removal (1.2 U/kg insulin, intraperitoneal) (15–17 weeks of age) of AgRP (E and G) and POMC (F and H) studies, respectively. AgRP and POMC data are from female and male mice, respectively, and are shown as means ± SEM (n = 3–9/group). P > 0.05 for all experiments applying ANCOVA or repeated measures two-way ANCOVA. Logarithmic transformations were done for GTT values of AgRP study and ITT values of POMC study. Controls represent GluN2Bflox/flox mice. NS: Not significant.
Mentions: Because AgRP and POMC neurons can respond to glucose and orchestrate blood glucose control [7,13,43,47], we measured fed glucose levels and performed glucose (GTT) and insulin (ITT) tolerance tests in young body-weight matched mice. GluN2B deletion in AgRP and POMC neurons did not affect fed blood glucose or serum insulin levels (Figure 5A–D), GTTs (AUC [AgRP]: 20.2 ± 0.76 × 103 and 24.1 ± 1.48 × 103 AgRP-GluN2B KO vs control, P > 0.05. AUC [POMC]: 31.6 ± 2.63 × 103 and 30.5 ± 1.40 × 103 POMC-GluN2B KO vs control, P > 0.05) (Figure 5E and F) or ITTs (AAC [AgRP]: 9.19 ± 0.97 × 103 and 9.12 ± 0.71 × 103 AgRP-GluN2B KO vs control, P > 0.05. AAC [POMC]: 7.46 ± 0.84 × 103 and 10.8 ± 1.60 × 103 POMC-GluN2B KO vs control, P > 0.05) (Figure 5G and H).

Bottom Line: NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function.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.Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus