Beneficial Effects of (pGlu-Gln)-CCK-8 on Energy Intake and Metabolism in High Fat Fed Mice are Associated with Alterations of Hypothalamic Gene Expression

Cholecystokinin (CCK) is a gastrointestinal hormone with potential therapeutic promise for obesity-diabetes. The present study examined the effects of twice daily administration of the N-terminally modified stable CCK-8 analogue, (pGlu-Gln)-CCK-8, on metabolic control and hypothalamic gene expression in high fat fed mice. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8 for 16 days significantly decreased body weight (p < 0.05), energy intake (p < 0.01), circulating blood glucose (p < 0.001), and plasma insulin (p < 0.001) compared to high fat controls. Furthermore, (pGlu-Gln)-CCK-8 markedly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.05). Assessment of hypothalamic gene expression on day 16 revealed significantly elevated NPY (p < 0.05) and reduced POMC (p < 0.05) and MC4R (p < 0.05) mRNA expression in (pGlu-Gln)-CCK-8 treated mice. High fat feeding or (pGlu-Gln)-CCK-8 treatment had no significant effects on hypothalamic gene expression of receptors for leptin, CCK 1 and GLP-1. These studies underscore the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes and suggest modulation of NPY and melanocortin related pathways may be involved in the observed beneficial effects.