Nibbling at CRF receptor control of feeding and gastrocolonic motility

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Abstract

Inadequate pharmacological tools, until recently, hindered the understanding of the roles of corticotropin-releasing factor (CRF) receptor subtypes in appetite regulation and gastrocolonic motor function. Now, novel ligands that are selective for CRF1 or CRF2 receptors are helping to uncover the specific functions of CRF receptor subtypes. Central or peripheral CRF2 receptor activation suppresses feeding independently of CRF1 receptors. In the rat, central administration of CRF2 receptor agonists promotes satiation without eliciting the malaise, behavioral arousal or anxiogenesis associated with CRF1 receptor agonists. Conversely, central administration of CRF1 receptor agonists elicits short-onset anorexia independently of CRF2 receptor activation. With respect to gastrointestinal motor function, stress inhibits gastric motility through CRF2 receptor-dependent central autonomic and peripheral myenteric systems. By contrast, stress stimulates colonic motility via CRF1 receptor-dependent sacral parasympathetic and colonic myenteric mechanisms. These findings have important physiological implications and suggest targeted approaches for the pharmacotherapy of obesity and stress-related functional gastrointestinal and eating disorders.

Section snippets

Selective CRF2 receptor ligands

The discovery of endogenous selective CRF2 receptor agonists – the type 2 urocortins (Ucn 2 [9] and Ucn 3 [10]) – opened a new chapter in our understanding of the functional significance of CRF systems in the brain and gut. Because the separate pro-hormones that contain the type 2 urocortins were identified using molecular cloning and database trawling strategies, the existence and structure of the mature peptides remain predicted, rather than known. Evidence 3, 4 favours the 38 amino acid

Satiation-like effects of brain and gut CRF2 receptor activation

In vivo studies with CRF2 receptor ligands suggest an anorectic role for gut CRF2 receptors. The anorectic effects of peripheral Ucn 1, which has been shown to suppress fasting-induced ingestion more potently than does CRF, CCK-8 or leptin [21], were attenuated by intraperitoneal (i.p.) injection of ASVG-30 [21] but not by selective CRF1 receptor antagonists 21, 22. Similarly, i.p. injection of stresscopin and stresscopin-related peptide (CRF2 receptor-selective analogues of Ucn 3 and Ucn 2,

CRF1 versus CRF2 receptor-mediated anorexia

Activation of CRF1 receptors in the brain can suppress feeding independently of CRF2 receptor-mediated mechanisms. For example, selective CRF1 receptor antagonists reverse at least some forms of stress-induced anorexia [26]. CRF1 and CRF2 receptor-mediated anorexia appear to exhibit different time-courses. In rats, i.c.v. administration of CRF1 receptor agonists elicited abbreviated, short-onset anorexia, CRF2 receptor agonists provoked delayed-onset anorexia, and nonselective CRF receptor

Stress inhibits gastric motility via brain and gut CRF2 receptor activation

In addition to their anorectic effects, stressors inhibit gastric motor function in a manner that is reversible by central pretreatment with nonselective CRF receptor antagonists 27, 28. Central administration of nonselective CRF receptor agonists has also been shown to delay gastric meal emptying [27]. Through vagal mechanisms, central infusion of nonselective CRF receptor agonists has been shown to reduce antral gastric motility, inhibit high-amplitude gastric contractions, and shift duodenal

Stress stimulates colonic motility via CRF1 receptor activation

In contrast to the inhibition of gastric motility, diverse stressors stimulate colonic motor function, manifesting as increased colonic motility, decreased colonic transit time, stimulated fecal output and watery diarrhoea. Central and peripheral administration of nonselective or preferential CRF1 27, 28, 35, but not CRF2 28, 32, receptor agonists, produces stress-like effects on colonic activity. Conversely, selective CRF1, but not CRF2, receptor antagonists attenuate stress- 27, 35, 36, 37 or

Physiological relevance of brain and gut CRF2 receptors

Discovered for their hypophysiotropic role in the endocrine stress response, CRF and the CRF1 receptor are commonly viewed as mediators that integrate the organism response to stress, a perspective consistent with the reviewed role of CRF1 receptors in stress-induced stimulation of colonic motility. By association, stress-related properties are often expected for the urocortins and the CRF2 receptor. Figure 3 outlines a proposed framework for understanding the adaptive roles of CRF-related

Acknowledgments

E.P.Z. and G.F.K. were supported by NIH DK26741. Y.T.'s work was supported by NIH DK33061, NIH DK57238 and a VA merit award. We gratefully recognize the editorial assistance of Mike Arends. This is publication number 15648-NP from The Scripps Research Institute.

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