title: 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.
abstract: 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, CCK₁ 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.
authors: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
authors: I A
authors: IA
authors: Montgomery
authors: N
authors: N
authors: Irwin
authors: P R
authors: PR
authors: Flatt
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002766:Cholecystokinin / Q000008:administration & dosage*; D059305:Diet, High-Fat / Q000009:adverse effects; D002149:Energy Intake / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; C574273:MC4R protein, mouse; D010446:Peptide Fragments; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; C410885:cholecystokinin 8; D011333:Pro-Opiomelanocortin; D052216:Glucagon-Like Peptide 1; D002766:Cholecystokinin