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Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

International Journal of Obesity Supplements volume 6, pages S22–S27 (2016)Cite this article

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Abstract

The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety. There has been interest in targeting the type 1 CCK receptor (CCK1R) for drug development to provide non-caloric satiation as an aid to dieting and weight loss; however, there have been concerns about CCK1R agonists related to side effects and potential trophic impact on the pancreas. A positive allosteric modulator (PAM) of CCK action at this receptor without intrinsic agonist activity could provide a safer and more effective approach to long-term administration. In addition, CCK1R stimulus–activity coupling has been shown to be negatively affected by excess membrane cholesterol, a condition described in the metabolic syndrome, thereby potentially interfering with an important servomechanism regulating appetite. A PAM targeting this receptor could also potentially correct the negative impact of cholesterol on CCK1R function. We will review the molecular basis for binding natural peptide agonist, binding and action of small molecules within the allosteric pocket, and the impact of cholesterol. Novel strategies for taking advantage of this receptor for the prevention and management of obesity will be reviewed.

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Acknowledgements

This work was supported by a grant from the National Institutes of Health (DK032878) and by the Mayo Clinic. Publication of this article was sponsored by the Université Laval’s Research Chair in Obesity in an effort to inform the public on the causes, consequences, treatments and prevention of obesity.

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  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, USA

    A J Desai, M Dong, K G Harikumar & L J Miller

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Desai, A., Dong, M., Harikumar, K. et al. Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor. Int J Obes Supp 6 (Suppl 1), S22–S27 (2016). https://doi.org/10.1038/ijosup.2016.5

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