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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

GluN2A in AgRP and POMC neurons is not required for normal body weight and energy intake. (A and C) Body weight (A) and cumulative food intake (C) (weeks 3–12) of control (GluN2Aflox/flox) and AgRP-GluN2A KO female mice. (B and D) Body weight (B) and cumulative food intake (D) at week 12 of control (GluN2Aflox/flox) and POMC-GluN2A KO female mice. Data are shown as means ± SEM (n = 7/group). NS: Not significant.
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fig3: GluN2A in AgRP and POMC neurons is not required for normal body weight and energy intake. (A and C) Body weight (A) and cumulative food intake (C) (weeks 3–12) of control (GluN2Aflox/flox) and AgRP-GluN2A KO female mice. (B and D) Body weight (B) and cumulative food intake (D) at week 12 of control (GluN2Aflox/flox) and POMC-GluN2A KO female mice. Data are shown as means ± SEM (n = 7/group). NS: Not significant.

Mentions: Intrahypothalamic injection of NMDAR/GluN2B agonists or antagonists elicits rapid feeding responses [26–28]. Furthermore, GluN1 deletion from AgRP neurons causes reductions in body weight, food intake, and body fat mass in mice [14]. Yet the role of specific GluN2 subunits within key hypothalamic neuronal groups remains unknown. We here examined whether GluN2A and GluN2B subunits in AgRP and POMC neurons are important for energy homeostasis control. We observed that mice lacking GluN2B in AgRP neurons had reduced body weight (Figure 1A and B), and cumulative food intake (Figure 1C and D) in male and female mice. Fat mass (Figure 1E) and blood leptin levels (Figure 1F) were also decreased in female mice. Male AgRP-GluN2B KO mice also exhibited lower fat mass relative to controls (2.75 ± 0.68 g; 4.66 ± 0.61 g; P = 0.07), although not quiet reaching statistical significance. In contrast, GluN2B deletion in POMC neurons did not affect body weight, food intake, body composition or leptin levels (Figure 2A–D). These results suggest that NMDAR GluN2B subunits in AgRP neurons are required for normal regulation of body weight homeostasis. In contrast, GluN2A neuron specific deletion from AgRP or POMC neurons did not affect body weight and food intake (Figure 3A–D). We therefore did not proceed with further studies of mice lacking GluN2A.


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)

GluN2A in AgRP and POMC neurons is not required for normal body weight and energy intake. (A and C) Body weight (A) and cumulative food intake (C) (weeks 3–12) of control (GluN2Aflox/flox) and AgRP-GluN2A KO female mice. (B and D) Body weight (B) and cumulative food intake (D) at week 12 of control (GluN2Aflox/flox) and POMC-GluN2A KO female mice. Data are shown as means ± SEM (n = 7/group). NS: Not significant.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588453&req=5

fig3: GluN2A in AgRP and POMC neurons is not required for normal body weight and energy intake. (A and C) Body weight (A) and cumulative food intake (C) (weeks 3–12) of control (GluN2Aflox/flox) and AgRP-GluN2A KO female mice. (B and D) Body weight (B) and cumulative food intake (D) at week 12 of control (GluN2Aflox/flox) and POMC-GluN2A KO female mice. Data are shown as means ± SEM (n = 7/group). NS: Not significant.
Mentions: Intrahypothalamic injection of NMDAR/GluN2B agonists or antagonists elicits rapid feeding responses [26–28]. Furthermore, GluN1 deletion from AgRP neurons causes reductions in body weight, food intake, and body fat mass in mice [14]. Yet the role of specific GluN2 subunits within key hypothalamic neuronal groups remains unknown. We here examined whether GluN2A and GluN2B subunits in AgRP and POMC neurons are important for energy homeostasis control. We observed that mice lacking GluN2B in AgRP neurons had reduced body weight (Figure 1A and B), and cumulative food intake (Figure 1C and D) in male and female mice. Fat mass (Figure 1E) and blood leptin levels (Figure 1F) were also decreased in female mice. Male AgRP-GluN2B KO mice also exhibited lower fat mass relative to controls (2.75 ± 0.68 g; 4.66 ± 0.61 g; P = 0.07), although not quiet reaching statistical significance. In contrast, GluN2B deletion in POMC neurons did not affect body weight, food intake, body composition or leptin levels (Figure 2A–D). These results suggest that NMDAR GluN2B subunits in AgRP neurons are required for normal regulation of body weight homeostasis. In contrast, GluN2A neuron specific deletion from AgRP or POMC neurons did not affect body weight and food intake (Figure 3A–D). We therefore did not proceed with further studies of mice lacking GluN2A.

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