دورية أكاديمية
Central insulin signaling modulates hypothalamus-pituitary-adrenal axis responsiveness.
| العنوان: | Central insulin signaling modulates hypothalamus-pituitary-adrenal axis responsiveness. |
|---|---|
| المؤلفون: | Chong AC; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA., Vogt MC; Max-Planck-Institute for Metabolism Research, 50931 Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany., Hill AS; Division of Integrative Neuroscience, Departments of Neuroscience and Psychiatry, Department of Pharmacology, Columbia University New York, NY 10032, USA., Brüning JC; Max-Planck-Institute for Metabolism Research, 50931 Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany ; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany., Zeltser LM; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA ; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. |
| المصدر: | Molecular metabolism [Mol Metab] 2014 Dec 10; Vol. 4 (2), pp. 83-92. Date of Electronic Publication: 2014 Dec 10 (Print Publication: 2015). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: eCollection Cited Medium: Print ISSN: 2212-8778 (Print) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: [München] : Elsevier GmbH, 2012- |
| مستخلص: | Objective: Obesity is often accompanied by hyperactivity of the neuroendocrine stress axis and has been linked to an increased risk of psychiatric disorders. Insulin is reciprocally regulated with the stress hormone corticosterone (CORT), raising the possibility that insulin normally provides inhibitory tone to the hypothalamus-adrenal-pituitary (HPA) axis. Here we examined whether disrupting signaling via the insulin receptor (InsR) in hypothalamic subpopulations impacts the neuroendocrine response to acute psychological stress. Methods: We used Nkx2.1-Cre, Sim1-Cre and Agrp-Cre transgenic driver lines to generate conditional knockouts of InsR signaling throughout the hypothalamus, paraventricular nucleus of the hypothalamus (PVH) and in neurons expressing Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARH), respectively. We used a combination of molecular, behavioral and neuroendocrine criteria to evaluate the consequences on HPA axis responsiveness. Results: Endpoints related to body weight and glucose homeostasis were not altered in any of the conditional mutant lines. Consistent with observations in the neuronal Insr knockout mice (NIRKO), baseline levels of serum CORT were similar to controls in all three lines. In male mice with broad disruptions of InsR signals in Nkx2.1-expressing regions of the hypothalamus (IR(Nkx2.1) KO), we observed elevated arginine vasopressin (AVP) levels at baseline and heightened neuroendocrine responses to restraint stress. IR(Nkx2.1) KO males also exhibited increased anxiety-like behaviors in open field, marble burying, and stress-induced hyperthermia testing paradigms. HPA axis responsivity was not altered in IR(Sim1) KO males, in which InsR was disrupted in the PVH. In contrast to observations in the IR(Nkx2.1) KO males, disrupting InsR signals in ARH neurons expressing Agrp (IR(Agrp) KO) led to reduced AVP release in the median eminence (ME). Conclusions: We find that central InsR signals modulate HPA responsivity to restraint stress. InsR signaling in AgRP/NPY neurons appears to promote AVP release, while signaling in other hypothalamic neuron(s) likely acts in an opposing fashion. Alterations in InsR signals in neurons that integrate metabolic and psychiatric information could contribute to the high co-morbidity of obesity and mental disorders. |
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| معلومات مُعتمدة: | P30 DK026687 United States DK NIDDK NIH HHS; P30 DK063608 United States DK NIDDK NIH HHS; R01 DK089038 United States DK NIDDK NIH HHS; T32 HD007430 United States HD NICHD NIH HHS |
| فهرسة مساهمة: | Keywords: ACTH, adrenocorticotropic hormone; ARH, arcuate nucleus of the hypothalamus; AVP, arginine vasopressin; AgRP; AgRP, agouti-related peptide; CORT, corticosterone; CRH, corticotropin-releasing hormone; FST, forced swim test; Gr, Glucocorticoid receptor; HPA axis; HPA axis, Hypothalamus–Pituitary–Adrenal axis; Hypothalamus; IRAgrp KO, knockout of InsR using Agrp-Cre; IRNkx2.1 KO, knockout of InsR using Nkx2.1-Cre; IRSim1 KO, knockout of InsR using Sim1-Cre; InsR, insulin receptor; Insulin; MB, marble burying test; MBH, mediobasal hypothalamus; ME, median eminence; NPY, neuropeptide Y; NSF, novelty suppressed feeding test; OF, open field test; POMC, pro-opiomelanocortin; SIH, stress-induced hyperthermia test; Stress response |
| تواريخ الأحداث: | Date Created: 20150217 Date Completed: 20150216 Latest Revision: 20181113 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC4314547 |
| DOI: | 10.1016/j.molmet.2014.12.001 |
| PMID: | 25685696 |
| قاعدة البيانات: | MEDLINE |
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