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Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.

ABSTRACT: Corticotropin-releasing factor (CRF) mediates our body's overall responses to stress. The role of central CRF in stress-stimulated colonic motility is well characterized. We hypothesized that transient perturbation in expression of enteric CRF is sufficient to change stress-induced colonic motor and secretory responses.Sprague-Dawley rats (adult, male) were subjected to 1-h partial restraint stress (PRS) and euthanized at 0, 4, 8, and 24 h. CRF mRNA and peptide levels in the colon were quantified by real-time RT-PCR, enzyme immuno-assay and immunohistochemistry. Double-stranded RNA (dsRNA) designed to target CRF (dsCRF) was injected into the colonic wall to attain RNA interference-mediated inhibition of CRF mRNA expression. DsRNA for ?-globin was used as a control (dsControl). Four days after dsRNA injection, rats were subjected to 1-h PRS. Fecal output was measured. Ussing chamber techniques were used to assess colonic mucosal ion secretion and transepithelial tissue conductance.Exposure to PRS elevated CRF expression and increased CRF release in the rat colon. Injection of dsCRF inhibited basal CRF expression and prevented the PRS-induced increase in CRF expression, whereas CRF expression in dsControl-injected colons remained high after PRS. In rats treated with dsControl, PRS caused a significant increase in fecal pellet output, colonic baseline ion secretion, and transepithelial tissue conductance. Inhibition of CRF expression in the colon prevented PRS-induced increase in fecal output, baseline ion secretion, and transepithelial tissue conductance.These results provide direct evidence that transient perturbation in peripherally expressed CRF prevents colonic responses to stress.

SUBMITTER: Liu S

PROVIDER: S-EPMC4727995 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.

Liu S S Chang J J Long N N Beckwith K K Talhouarne G G Brooks J J JJ Qu M-H MH Ren W W Wood J D JD Cooper S S Bhargava A A

Neurogastroenterology and motility 20151126 2

<h4>Background</h4>Corticotropin-releasing factor (CRF) mediates our body's overall responses to stress. The role of central CRF in stress-stimulated colonic motility is well characterized. We hypothesized that transient perturbation in expression of enteric CRF is sufficient to change stress-induced colonic motor and secretory responses.<h4>Methods</h4>Sprague-Dawley rats (adult, male) were subjected to 1-h partial restraint stress (PRS) and euthanized at 0, 4, 8, and 24 h. CRF mRNA and peptide ...[more]

PMID: 26611915

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Project description:The chronic inability of alcoholics to effectively cope with relapse-inducing stressors has been linked to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and corticotropin-releasing factor (CRF) signaling. However, the cellular mechanisms responsible for this dysregulation are yet to be identified. After exposure of male Sprague Dawley rats to chronic intermittent ethanol (CIE; 5-6 g/kg orally for 35 doses over 50 days) or water, followed by 40-60 days of protracted withdrawal, we investigated CIE effects on glutamatergic synaptic transmission, stress-induced plasticity, CRF- and ethanol-induced NMDAR inhibition using electrophysiological recordings in parvocellular neurosecretory cells (PNCs) of the paraventricular nucleus. We also assessed CIE effects on hypothalamic mRNA expression of CRF-related genes using real-time polymerase chain reaction, and on HPA axis function by measuring stress-induced increases in plasma adrenocorticotropic hormone, corticosterone, and self-grooming. In control rats, ethanol-mediated inhibition of NMDARs was prevented by CRF1 receptor (CRFR1) blockade with antalarmin, while CRF/CRFR1-mediated NMDAR blockade was prevented by intracellularly-applied inhibitor of phosphatases PP1/PP2A, okadaic acid, but not the selective striatal-enriched tyrosine protein phosphatase inhibitor, TC-2153. CIE exposure increased GluN2B subunit-dependent NMDAR function of PNCs. This was associated with the loss of both ethanol- and CRF-mediated NMDAR inhibition, and loss of stress-induced short-term potentiation of glutamatergic synaptic inputs, which could be reversed by intracellular blockade of NMDARs with MK801. CIE exposure also blunted the hormonal and self-grooming behavioral responses to repeated restraint stress. These findings suggest a cellular mechanism whereby chronic alcohol dysregulates the hormonal and behavioral responses to repetitive stressors by increasing NMDAR function and decreasing CRFR1 function.

Project description:BackgroundChronic stress is a major contributor in the development of metabolic syndrome and associated diseases, such as diabetes. High-fat diet (HFD) and sex are known modifiers of metabolic parameters. Peptide hormones corticotropin-releasing factor (CRF) and urocortins (UCN) mediate stress responses via activation and feedback to the hypothalamic-pituitary-adrenal (HPA) axis. UCN3 is a marker of pancreatic β-cell differentiation, and UCN2 is known to ameliorate glucose levels in mice rendered diabetic with HFD. CRF receptor 2 (CRF2) is the only known cognate receptor for UCN2/3. Here, we ascertained the role of CRF2 in glucose clearance, insulin sensitivity, and other parameters associated with metabolic syndrome in a mouse model of nutritional stress.MethodsWild-type (WT) and Crhr2-/- (null) mice of both sexes were fed either normal chow diet or HFD. After 8 weeks, blood glucose levels in response to glucose and insulin challenge were determined. Change in body and fat mass, plasma insulin, and lipid profile were assessed. Histological evaluation of liver sections was performed.ResultsHere, we show that genotype (Crhr2), sex, and diet were all independent variables in the regulation of blood glucose levels, body and fat mass gain/redistribution, and insulin resistance. Surprisingly, CRF2-deficient mice (Crhr2-/-) male mice showed similarly impaired glucose clearance on HFD and chow. HFD-fed female Crhr2-/- mice redistributed their fat depots that were distinct from wild-type females and male mice on either diet. Blood cholesterol and low-density lipoprotein (LDL) levels were elevated significantly in male Crhr2-/- mice; female Crhr2-/- mice were protected. Male, but not female Crhr2-/- mice developed peripheral insulin resistance. HFD, but not chow-fed wild-type male mice developed hepatic macrovesicular steatosis. In contrast, livers of Crhr2-/- male mice showed microvesicular steatosis on either diet, whereas livers of female mice on this 8-week HFD regimen did not develop steatosis.ConclusionsCRF2 receptor dysregulation is a sexually dimorphic risk factor in development of pre-diabetic and metabolic symptoms.

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Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.

Publications

Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.

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