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Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

Irwin, Nigel, Montgomery, IA and Flatt, Peter (2013) Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice. Diabetologia, 56 (6). pp. 1425-1435. [Journal article]

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URL: http://www.ncbi.nlm.nih.gov/pubmed/23462797

DOI: 10.1007/s00125-013-2878-0

Abstract

AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively.METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice.RESULTS: (pGlu-Gln)-CCK-8 had prominent (p < 0.01 to p < 0.001), acute feeding-suppressive effects, which were significantly augmented (p < 0.05 to p < 0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p < 0.05 to p < 0.001), energy intake (p < 0.01), circulating triacylglycerol (p < 0.01), non-fasting glucose (p < 0.05 to p < 0.001) and triacylglycerol deposition in liver and adipose tissue (p < 0.001). All treatment regimens improved glucose tolerance (p < 0.05 to p < 0.001) and insulin sensitivity (p < 0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p < 0.001) energy expenditure.CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:25162
Deposited By: Dr Nigel Irwin
Deposited On:11 Mar 2013 14:15
Last Modified:09 May 2016 11:15

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