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

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.International Journal of Obesity Supplements (2016) 6, S22-S27; doi:10.1038/ijosup.2016.5 INTRODUCTIONThe prevalence of obesity has been progressively increasing throughout the United States and around the world, contributing to a parallel increase in the prevalence of type 2 diabetes mellitus and its associated comorbidities. 1 These problems have been responsible for extraordinary morbidity, suffering, loss in productivity and premature mortality. In spite of major efforts to develop effective weight reduction diets, diet aids, medications, medical devices and surgical procedures, the trajectory for this continues in the wrong direction. Bariatric surgery has proven to be quite effective in patients with morbid obesity; 2 however, this is quite expensive and not scalable, certainly not keeping up with the increasing prevalence of the most severe end of this clinical continuum. The activity of acute dieting and exercise has been similarly effective in inducing weight loss; however, it has not been durable, with an extremely high incidence of regaining weight to or even beyond the starting point. After a long hiatus in approved drugs, three new diet medications have recently been approved, 3-5 but all carry concerns about safety, and there are requirements for registration and careful clinical follow-up, re...

Effect of High Fat Diet on Weight Loss Through the Expression of Uncouple Protein 1 in Mice Visceral Fat

“…HFD supplementation was also reported to secrete cholecystokinin (CCK), that responds to the intake of fat and protein. The hormone stimulates satiety after food consumption (Desai et al, 2016). The secretion CCK, which manipulates hunger, can be a tool to reduce the amount of food taken in by the body and reduce body weight, which works by preventing a positive energy balance, where the energy consumed is of greater amount compared to body metabolism and physical activity (Romieu et al, 2017).…”

Roles of Cholecystokinin in the Nutritional Continuum. Physiology and Potential Therapeutics

“…The allosteric modulatory effects are typically saturable, adding an additional level of safety to the effects of these agents. It has previously been suggested that pure allosteric modulators may be advantageous as CCK1R-active drugs to be used in obesity ( 34 ) - a positive allosteric modulator of CCK1R possessing no intrinsic agonist activity could enhance the satiety effect of natural CCK when it is released after a meal ( 34 ). The short half-life of circulating CCK peptides would limit the potential for side-effects relating to prolonged receptor activation, adding to the safety profile of such agents.…”

Metabolic Hormones Modulate Macrophage Inflammatory Responses

“…The peptide hormone Cholecystokinin (CCK) is well-established as being a metabolic hormone secreted from I cells of the small intestine when high levels of dietary fatty acids or proteins are detected [ 14 ]. CCK regulates digestion by stimulating the release of digestive enzymes and insulin from the pancreas and mediates satiety by binding to CCK receptors in the vagal afferent neurons of the gut–brain axis [ 15 ]. However, CCK is also a neurotransmitter, growth factor and anti-inflammatory cytokine expressed as multiple different bioactive peptides by neurons, endocrine, and epithelial cells (recently reviewed in [ 16 ]).…”