Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

Abstract

Cholecystokinin regulates appetite and reduces food intake by activating the type 1 CCK receptor (CCK1R). Attempts to develop CCK1R agonists for obesity have yielded active agents that have not reached clinical practice. In this review we discuss why, along with new strategies to target CCK1R more effectively. We examine signaling events and the possibility of developing agents that exhibit ligand-directed bias, to dissociate satiety activity from undesirable side effects. Potential allosteric sites of modulation are also reviewed, along with desired properties of a positive allosteric modulator without intrinsic agonist action as another strategy to treat obesity. These new types of CCK1R-active drugs could be useful as stand-alone agents or as part of a rational drug combination for management of obesity.

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons

“…Impaired satiety signaling in the gastrointestinal tract becomes important in initiating weight gain and obesity (4). Gut peptide hormones released in response to food intake and related satiety signals conducted by vagal afferent neurons have become potential targets for future therapeutic intervention (5,6).…”

“…Sensitivity to anorexigenic vagal signals such as mechanical distention, leptin, PYY, GLP-1, and CCK is reduced. CCK is a major paracrine satiety hormone secreted after intake of fat and protein (5,7,9). Its suppressive effect on food intake is reduced in obesity (10,11).…”

“…Its suppressive effect on food intake is reduced in obesity (10,11). Administration of CCK decreases meal size and increases meal duration (5,7,12,13). Conversely, administration of a CCK1 (CCKA) receptor antagonist decreases feelings of fullness and increases meal size in humans (5,14).…”

“…Administration of CCK decreases meal size and increases meal duration (5,7,12,13). Conversely, administration of a CCK1 (CCKA) receptor antagonist decreases feelings of fullness and increases meal size in humans (5,14). Activation of intestinal vagal afferents by CCK through CCK1 (CCKA) receptor transduces the short-term satiety signal to the nucleus tractus solitarius (NTS) and hypothalamus to terminate food intake and, in addition, increases metabolism and limits weight gain (15,16).…”

The pathophysiological role of cholecystokinin‐1 receptor in mouse cholelithogenesis

“…Known as neuropeptide hormone, CCK-1R has been shown to modulate several pathophysiological processes involving cardiovascular system and malignancy progression [5,6,7]. The inhibition of CCK-1R has then been suggested for the treatment of many gastrointestinal disorders and, more recently, as potential strategy to treat obesity [8]. Furthermore, many pharmacological studies are elucidating the molecular basis of CCK-1R antagonism, so that new selective drugs are expected to be developed in the near future [9].…”