Limits...
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 from AgRP and POMC neurons: Neuron numbers (A–F) Representative microphotographs (hrGFP immunohistochemistry) and cell counts of AgRP (A and C) and POMC (B and D) neurons in brain sections from body weight-matched (E and F) male control and KO animals (8 weeks of age). Data in Figure 8C and D are presented as the mean neuron number ± SEM (n = 4–5 mice/group). Differences between groups were evaluated with Student's t test. NS: Not significant. ARC: Arcuate nucleus. 3V: Third ventricle. Images in (A) and (B) were captured at 20× magnification.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4588453&req=5

fig7: Deletion of GluN2B from AgRP and POMC neurons: Neuron numbers (A–F) Representative microphotographs (hrGFP immunohistochemistry) and cell counts of AgRP (A and C) and POMC (B and D) neurons in brain sections from body weight-matched (E and F) male control and KO animals (8 weeks of age). Data in Figure 8C and D are presented as the mean neuron number ± SEM (n = 4–5 mice/group). Differences between groups were evaluated with Student's t test. NS: Not significant. ARC: Arcuate nucleus. 3V: Third ventricle. Images in (A) and (B) were captured at 20× magnification.

Mentions: NMDARs play a key role in neuron survival, neuronal plasticity and dendritic development, and even short-term blockade of NMDARs can trigger rapid neurodegeneration in the brain [35]. Therefore, since mice lacking GluN2B subunits in AgRP neurons have altered feeding behavior, we examined the number of AgRP neurons and assessed dendritic morphology in AgRP-GluN2B KO mice. To avoid potential indirect effects due to differences in body weight, body weight-matched KO and control mice were pre-selected for these studies (Figure 7E and F). We found that loss of GluN2B subunits from AgRP neurons caused a marked decrease (∼35%) in the number of AgRP neurons (Figure 7A and C). In contrast, deletion of GluN2B from POMC neurons did not affect hypothalamic POMC cell numbers (Figure 7B and D). In addition, GluN2B deletion from AgRP neurons resulted in a decrease (∼40%) in AgRP dendritic length (Figure 8A and B), also independently of body weight (Figure 8C). These data suggest that GluN2B NMDARs in hypothalamic AgRP neurons influence cell number and dendritic morphology. Therefore, the reduced body weight and energy intake of mice lacking GluN2B in AgRP neurons may be caused, at least in part by reduced neuronal survival and/or by altered dendritic morphology.


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 from AgRP and POMC neurons: Neuron numbers (A–F) Representative microphotographs (hrGFP immunohistochemistry) and cell counts of AgRP (A and C) and POMC (B and D) neurons in brain sections from body weight-matched (E and F) male control and KO animals (8 weeks of age). Data in Figure 8C and D are presented as the mean neuron number ± SEM (n = 4–5 mice/group). Differences between groups were evaluated with Student's t test. NS: Not significant. ARC: Arcuate nucleus. 3V: Third ventricle. Images in (A) and (B) were captured at 20× magnification.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

fig7: Deletion of GluN2B from AgRP and POMC neurons: Neuron numbers (A–F) Representative microphotographs (hrGFP immunohistochemistry) and cell counts of AgRP (A and C) and POMC (B and D) neurons in brain sections from body weight-matched (E and F) male control and KO animals (8 weeks of age). Data in Figure 8C and D are presented as the mean neuron number ± SEM (n = 4–5 mice/group). Differences between groups were evaluated with Student's t test. NS: Not significant. ARC: Arcuate nucleus. 3V: Third ventricle. Images in (A) and (B) were captured at 20× magnification.
Mentions: NMDARs play a key role in neuron survival, neuronal plasticity and dendritic development, and even short-term blockade of NMDARs can trigger rapid neurodegeneration in the brain [35]. Therefore, since mice lacking GluN2B subunits in AgRP neurons have altered feeding behavior, we examined the number of AgRP neurons and assessed dendritic morphology in AgRP-GluN2B KO mice. To avoid potential indirect effects due to differences in body weight, body weight-matched KO and control mice were pre-selected for these studies (Figure 7E and F). We found that loss of GluN2B subunits from AgRP neurons caused a marked decrease (∼35%) in the number of AgRP neurons (Figure 7A and C). In contrast, deletion of GluN2B from POMC neurons did not affect hypothalamic POMC cell numbers (Figure 7B and D). In addition, GluN2B deletion from AgRP neurons resulted in a decrease (∼40%) in AgRP dendritic length (Figure 8A and B), also independently of body weight (Figure 8C). These data suggest that GluN2B NMDARs in hypothalamic AgRP neurons influence cell number and dendritic morphology. Therefore, the reduced body weight and energy intake of mice lacking GluN2B in AgRP neurons may be caused, at least in part by reduced neuronal survival and/or by altered dendritic morphology.

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