Dataset Information

Melanocortin-3 Receptors Expressed on Agouti-Related Peptide Neurons Inhibit Feeding Behavior in Female Mice.

ABSTRACT:

Objective

Activation of hypothalamic agouti-related peptide expressing (AgRP)^+ve neurons during energy deficit is a negative valence signal, rapidly activating food-seeking behaviors. This study examined the roles of melanocortin-3 receptors (MC3Rs) coexpressed in a subpopulation of AgRP^+ve neurons.

Methods

AgRP-MC3R mice expressing MC3Rs selectively in AgRP^+ve neurons were generated by crossing AgRP-IRES-Cre mice with LoxTBMc3r mice containing a "loxP-STOP-loxP" sequence in the 5' untranslated region. Body weight, body composition, and feeding behavior were assessed during ad libitum and time-restricted feeding conditions.

Results

In females, food intake of AgRP-IRES-Cre^+ve (n?=?7) or AgRP-IRES-Cre^-ve (n?=?9) mice was not significantly different; these mice were therefore pooled to form the "control" group. Female AgRP-MC3R mice exhibited lower food intake (25.4?±?2.4 kJ/12 h; n?=?6) compared with controls (35.3?±?1.8 kJ/12 h; n?=?16) and LoxTBMc3r mice (32.1?±?2.1 kJ/12 h; n?=?9) in the active phase during the dark period. Food intake during the rest phase (lights on) when mice consume less food (9-10 kJ) was normal between genotypes. Body weight and composition of AgRP-MC3R and LoxTBMc3r mice were similar, suggesting compensatory mechanisms for reduced calorie intake. Remarkably, AgRP-MC3R mice continued to consume less food during refeeding after fasting and time-restricted feeding.

Conclusions

MC3Rs expressed on AgRP^+ve neurons appear to exert a strong inhibitory signal on hypothalamic networks governing feeding behavior.

SUBMITTER: Girardet C

PROVIDER: S-EPMC7294842 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Melanocortin-3 Receptors Expressed on Agouti-Related Peptide Neurons Inhibit Feeding Behavior in Female Mice.

Girardet Clemence C Marks Daniel L DL Butler Andrew A AA

Obesity (Silver Spring, Md.) 20181114 12

<h4>Objective</h4>Activation of hypothalamic agouti-related peptide expressing (AgRP)<sup>+ve</sup> neurons during energy deficit is a negative valence signal, rapidly activating food-seeking behaviors. This study examined the roles of melanocortin-3 receptors (MC3Rs) coexpressed in a subpopulation of AgRP<sup>+ve</sup> neurons.<h4>Methods</h4>AgRP-MC3R mice expressing MC3Rs selectively in AgRP<sup>+ve</sup> neurons were generated by crossing AgRP-IRES-Cre mice with LoxTBMc3r mice containing a " ...[more]

PMID: 30426710

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Project description:When it comes to obesity, men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage wanes in postmenopausal women. A key diagnostic of the metabolic syndrome is insulin resistance in both peripheral tissues and brain, especially in the hypothalamus. Since the anorexigenic hormone 17?-estradiol (E2) regulates food intake in part by inhibiting the excitability of the hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, we hypothesized that E2 would protect against insulin resistance in NPY/AgRP neurons with diet-induced obesity (DIO). Therefore, we did whole-cell recordings and single cell quantitative polymerase chain reaction in arcuate NPYGFP neurons from both female and male mice to test the efficacy of insulin with DIO. The resting membrane potential and input resistance of NPY/AgRP neurons were significantly increased in DIO versus control-diet fed males. Most notably, the efficacy of insulin to activate KATP channels in NPY/AgRP neurons was significantly attenuated, although the KATP channel opener diazoxide was fully effective in NPY/AgRP neurons from DIO males, indicating that the KATP channels were expressed and functional. In contrast, insulin was fully efficacious to activate KATP channels in DIO females, and the response was reversed by the KATP channel blocker tolbutamide. However, the ability of insulin to activate KATP channels was abrogated with ovariectomy but fully restored with E2 replacement. Insulin resistance in obese males was likely mediated by an increase in suppressor of cytokine signaling-3 (SOCS-3), protein tyrosine phosphatase B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP) activity, since the expression of all 3 mRNAs were upregulated in the obese males but not in females. As proof of principle, pre-incubation of hypothalamic slices from DIO males with the PTP1B/TCPTP inhibitor CX08005 completely rescued the effects of insulin. Therefore, E2 protects NPY/AgRP neurons in females against insulin resistance through, at least in part, attenuating phosphatase activity. The neuroprotective effects of E2 may explain sex differences in the expression of metabolic syndrome that disappears with the loss of E2 in aging.

Dataset Information

Melanocortin-3 Receptors Expressed on Agouti-Related Peptide Neurons Inhibit Feeding Behavior in Female Mice.

Objective

Methods

Results

Conclusions

Publications

Melanocortin-3 Receptors Expressed on Agouti-Related Peptide Neurons Inhibit Feeding Behavior in Female Mice.

Similar Datasets

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