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Effect of the CRF1-receptor antagonist pexacerfont on stress-induced eating and food craving.

ABSTRACT: RATIONALE:In rodents, antagonism of receptors for corticotropin-releasing factor (CRF) blocks stress-induced reinstatement of drug or palatable food seeking. OBJECTIVE:To test anticraving properties of the CRF1 antagonist pexacerfont in humans. METHODS:We studied stress-induced eating in people scoring high on dietary restraint (food preoccupation and chronic unsuccessful dieting) with body-mass index (BMI) >22. In a double-blind, between-groups trial, 31 "restrained" eaters were stabilized on either pexacerfont (300 mg/day for 7 days, then 100 mg/day for 21 days) or placebo. On day 15, they underwent a math-test stressor; during three subsequent visits, they heard personalized craving-induction scripts. In each session, stress-induced food consumption and craving were assessed in a bogus taste test and on visual analog scales. We used digital video to monitor daily ingestion of study capsules and nightly rating of food problems/preoccupation on the Yale Food Addiction Scale (YFAS). RESULTS:The study was stopped early due to an administrative interpretation of US federal law, unrelated to safety or outcome. The bogus taste tests suggested some protective effect of pexacerfont against eating after a laboratory stressor (r effect = 0.30, 95 % CL = -0.12, 0.63, Bayes factor 11.30). Similarly, nightly YFAS ratings were lower with pexacerfont than placebo (r effect = 0.39, CI 0.03, 0.66), but this effect should be interpreted with caution because it was present from the first night of pill ingestion, despite pexacerfont's slow pharmacokinetics. CONCLUSIONS:The findings may support further investigation of the anticraving properties of CRF1 antagonists, especially for food.

SUBMITTER: Epstein DH

PROVIDER: S-EPMC5580374 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Effect of the CRF<sub>1</sub>-receptor antagonist pexacerfont on stress-induced eating and food craving.

Epstein David H DH Kennedy Ashley P AP Furnari Melody M Heilig Markus M Shaham Yavin Y Phillips Karran A KA Preston Kenzie L KL

Psychopharmacology 20160905 23-24

<h4>Rationale</h4>In rodents, antagonism of receptors for corticotropin-releasing factor (CRF) blocks stress-induced reinstatement of drug or palatable food seeking.<h4>Objective</h4>To test anticraving properties of the CRF<sub>1</sub> antagonist pexacerfont in humans.<h4>Methods</h4>We studied stress-induced eating in people scoring high on dietary restraint (food preoccupation and chronic unsuccessful dieting) with body-mass index (BMI) >22. In a double-blind, between-groups trial, 31 "restra ...[more]

PMID: 27595147

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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.

Dataset Information

Effect of the CRF1-receptor antagonist pexacerfont on stress-induced eating and food craving.

Publications

Effect of the CRF<sub>1</sub>-receptor antagonist pexacerfont on stress-induced eating and food craving.

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