Figure 7.

Model of CB1R control of nutrient-induced CCK release. Our studies suggest that cannabinoid CB₁Rs in the upper small-intestinal epithelium control nutrient-induced satiation signaling, and their signaling is increased in diet-induced obesity, which drives overeating by delaying satiation. The upper small-intestinal epithelium contains enteroendocrine I-cells, which are a subpopulation of enterocytes that secrete cholecystokinin (CCK) when nutrients – including dietary fats – enter the lumen (Rehfeld, 1998; Tanaka et al., 2008; Wang et al., 2011; Liou et al., 2011a; Brennan et al., 2012). Dietary fats (e.g., corn oil), in the form of triacylglycerols, are hydrolyzed in the lumen into mostly monoacylglycerols and free-fatty acids (FFAs) that are sensed by free-fatty acid receptors (FFARs) located on enteroendocrine cells in the small-intestinal epithelium. Activation of FFARs stimulates secretion of CCK by a mechanism that requires calcium (Ca²⁺) influx and/or intracellular (i.e., endoplasmic reticulum, ER) mobilization (McLaughlin et al., 1998; Hira et al., 2004; Tanaka et al., 2008). CCK activates CCK_A receptors located on adjacent afferent sensory vagal fibers, which in turn, communicate with the brain and control meal size and satiation (Smith et al., 1981, 1985; Schwartz and Moran, 1994; Kaelberer et al., 2018). Consumption of a Western diet (WD) is associated with increased levels of the endocannabinoids (eCBs) and their activity at CB₁Rs in the upper small-intestinal epithelium, which we propose inhibits CCK release and satiation signaling. The molecular mechanism(s) mediating CB₁R control of CCK release is unknown, but may include inhibition of Ca²⁺-mediated CCK release. A future test of this hypothesis is warranted.