Impaired hypothalamic insulin signaling in CUMS rats: restored by icariin and fluoxetine through inhibiting CRF system.
Epidemiological evidence demonstrates the neuroendocrine link between stress, depression and diabetes. This study observed glucose intolerance of rats exposed to chronic unpredictable mild stress (CUMS) in oral glucose tolerance test (OGTT). CUMS procedure significantly up-regulated corticotropin-releasing factor (CRF)-related peptide urocortin 2 expression and elevated cAMP production, resulting in over-expression of suppressor of cytokine signaling 3 (SOCS3) in hypothalamic arcuate nucleus (ARC) of rats. Furthermore, SOCS3 activation blocked insulin signaling pathway through the suppression of insulin receptor substrate 2 (IRS2) phosphotyrosine and phosphatidylinositol-3-kinase (PI3-K) activation in hypothalamic ARC of CUMS rats after high-level of insulin stimulation. These data indicated that CUMS procedure induced the hyperactivity of CRF system, and subsequently produced conditional loss of insulin signaling in hypothalamic ARC of rats. More importantly, icariin and fluoxetine with the ability to restrain CRF system hyperactivity improved insulin signaling in hypothalamic ARC of CUMS rats, which were consistent with the enhancement of glucose tolerance in OGTT, showing anti-diabetic efficacy. Although effective in OGTT, anti-diabetic drug pioglitazone failed to restore hypothalamic ARC CRF system hyperactivity, paralleling with its inability to ameliorate the loss of insulin signaling and depression-like behavior in CUMS rats. These observations support the hypothesis that signal cross-talk between hypothalamic CRF system and insulin may be impaired in depression with glucose intolerance and suggest that icarrin and fluoxetine aiming at CRF system may have great potential in the prevention and treatment of depression with comorbid diabetes.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
Ying
Y
Pan
Ye
Y
Hong
Qing-Yu
QY
Zhang
Ling-Dong
LD
Kong
D059445:Anhedonia; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002908:Chronic Disease; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000503:physiopathology / Q000523:psychology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects* / Q000503:physiopathology; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D054832:Urocortins / Q000096:biosynthesis / Q000235:genetics
D000928:Antidepressive Agents; D005419:Flavonoids; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; D054832:Urocortins; C518358:urocortin 2, mouse; D005473:Fluoxetine; D003346:Corticotropin-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases; C056599:icariin; D000077205:Pioglitazone