Metabolic effects of activation of CCK receptor signaling pathways by twice-daily administration of the enzyme-resistant CCK-8 analog, (pGlu-Gln)-CCK-8, in normal mice.

Cholecystokinin (CCK) is a hormone that has important physiological effects on energy balance. This study has used a stable CCK(1) receptor agonist, (pGlu-Gln)-CCK-8, to evaluate the metabolic effects of prolonged administration in normal mice. Twice-daily injection of (pGlu-Gln)-CCK-8 for 28 days resulted in significantly lowered body weights (P<0.05) on days 24 and 28, which was associated with decreased accumulated calorie intake (P<0.01) from day 12 onward. Nonfasting plasma glucose was significantly reduced (P<0.05) on day 28, while plasma insulin concentrations were increased (P<0.05). After 28 days, glucose tolerance and glucose-mediated insulin secretion were not significantly different in (pGlu-Gln)-CCK-8-treated mice. However, following a 15-min refeeding period in 18-h fasted mice, glucose levels were significantly (P<0.05) decreased by (pGlu-Gln)-CCK-8 despite similar food intake and nutrient-induced insulin levels. Insulin sensitivity in (pGlu-Gln)-CCK-8-treated mice was significantly (P<0.01) improved compared with controls. Accumulation of triacylglycerol in liver was reduced (P<0.01) but there were no differences in circulating cholesterol and triacylglycerol concentrations, as well as triacylglycerol content of pancreatic, muscle, and adipose tissue in (pGlu-Gln)-CCK-8 mice. These data highlight the beneficial metabolic effects of prolonged (pGlu-Gln)-CCK-8 administration and confirm a lack of detrimental effects.