title: Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice.
abstract: The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively. Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0.001), body weight (p < 0.01), circulating insulin and LDL-cholesterol (p < 0.001) and improved insulin sensitivity (p < 0.001) as well as oral and intraperitoneal (p < 0.001) glucose tolerance. Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls. In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle. Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0.001) elevated pancreatic glucagon content. Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0.001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1. Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0.05), body weight (p < 0.05 to p < 0.01), circulating glucose (p < 0.05 to p < 0.01) and insulin (p < 0.05 to p < 0.001) and improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Notably, these beneficial effects were still evident 18 days following cessation of treatment. These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Ian A
authors.initials: IA
authors.lastname: Montgomery
authors.forename: R Charlotte
authors.initials: RC
authors.lastname: Moffett
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D004041:Dietary Fats / Q000008:administration & dosage*; D004435:Eating / Q000187:drug effects; D005934:Glucagon / Q000032:analysis; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D010179:Pancreas / Q000737:chemistry / Q000473:pathology; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C578541:(pGlu-Gln)-CCK-8; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D011949:Receptors, Cholecystokinin; D005934:Glucagon; D012844:Sincalide