Cholecystokinin (CCK) is a peptide hormone secreted from enteroendocrine cells and regulates the exocrine pancreas, gastric motility, and appetite. Dietary triacylglycerols are hydrolyzed to fatty acids (FA) and 2‐monoacylglycerols (2‐MAG) in the small intestine. Although it is well known that FA stimulate CCK secretion, whether 2‐MAG have the CCK‐releasing activity remains unclear. We examined the CCK‐releasing activity of four commercially available 2‐MAG in a murine CCK‐producing cell line, STC‐1, and the molecular mechanism underlying 2‐MAG‐induced CCK secretion. CCK released from the cells was measured using ELISA. Among four 2‐MAG (2‐palmitoyl, 2‐oleoyl, 2‐linoleoyl, and 2‐arachidonoyl monoacylglycerols) examined, 2‐arachidonoyl glycerol (2‐AG) potently stimulated CCK secretion in a dose‐dependent manner. Structurally related compounds, such as 2‐arachidonoyl glycerol ether and 1‐arachidonoyl glycerol, did not stimulate CCK secretion. Both arachidonic acid and 2‐AG stimulated CCK secretion at 100 μM, but only 2‐AG did at 50 μM. 2‐AG‐induced CCK secretion but not arachidonic acid‐induced CCK secretion was attenuated by treatment with a cannabinoid receptor 1 (CB1) antagonist. These results indicate that a specific 2‐MAG, 2‐AG, directly stimulates CCK secretion via CB1.

2‐Monoacylglycerol (2‐MAG) is one of the digestion products of dietary lipids. We recently demonstrated that a 2‐MAG, 2‐arachidonoyl glycerol (2‐AG) potently stimulated cholecystokinin (CCK) secretion via cannabinoid receptor 1 (CB1) in a murine CCK‐producing cell line, STC‐1. CCK plays a crucial role in suppressing postprandial gastric emptying. To examine the effect of 2‐AG on gastric emptying, we performed acetaminophen and phenol red recovery tests under oral or intraperitoneal administration of 2‐AG in mice. Orally administered 2‐AG (25 mg/kg) suppressed the gastric emptying rate in mice, as determined by the acetaminophen absorption test and phenol red recovery test. Intraperitoneal administration of a cholecystokinin A receptor antagonist (0.5 mg/kg) attenuated the gastric inhibitory emptying effect. In addition, both oral (10 mg/kg) and intraperitoneal (0.5 mg/kg) administration of a CB1 antagonist counteracted the 2‐AG‐induced gastric inhibitory effect. Furthermore, intraperitoneal 2‐AG (25 mg/kg) suppressed gastric emptying. These results indicate that 2‐AG exhibits an inhibitory effect on gastric emptying in mice, possibly mediated by stimulating both CCK secretion via CB1 expressed in CCK‐producing cells and acting on CB1 expressed in the peripheral nerves. Our findings provide novel insights into the 2‐MAG‐sensing mechanism in enteroendocrine cells and the physiological role of 2‐MAG.

Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 h were measured using a thermocouple thermometer before and after an oral administration of nutrients. Oxygen consumption after oral protein administration was also measured in rats. Rectal temperature measurements in rats confirmed an increase in core body temperature after refeeding, and the thermic effect of the oral administration of protein was greater than that of a representative carbohydrate or lipid. Among the five dietary proteins examined (casein, whey, rice, egg, and soy), soy protein had the highest thermic effect. The thermic effect of soy protein was also demonstrated by increased oxygen consumption. Studies using a nonselective β-adrenergic receptor antagonist and thermal camera suggested that brown adipose tissue did not contribute to soy protein-induced increase in rectal temperature. Furthermore, the thermic effect of soy protein was completely abolished by antagonism and knockout of GLP-1 receptor, yet potentiated via augmentation of intact GLP-1 levels through inhibition of dipeptidyl peptidase-4 activity. These results indicate that GLP-1 signaling is essential for the thermic effects of dietary proteins in rats and mice, and extend the metabolic actions of GLP-1 ensuing from nutrient ingestion to encompass the thermic response to ingested protein.