Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1830, Issue 8, Pages 4009-4016Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2013.04.004
Keywords
Cholecystokinin (CCK); High fat; Obesity; Diabetes; PEGylation; Insulin sensitivity
Categories
Funding
- SAAD Trading and Contracting Company
- Department of Education and Learning, Northern Ireland
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Background: Cholecystokinin (CCK) is a gastrointestinal hormone that has been proposed as a potential therapeutic option for obesity-diabetes. As such, (pGlu-Gln)-CCK-8 is an N-terminally modified CCK-8 analogue with improved biological effectiveness over the native peptide. Methods: The current study has examined the in vitro stability, biological activity and in vivo therapeutic applicability of a novel second generation mini-PEGylated form of (pGlu-Gln)-CCK-8, (pGlu-Gln)-CCK-8[mPEG]. Results: (pGlu-Gln)-CCK-8[mPEG] was completely resistant to enzymatic degradation and in addition displayed similar insulinotropic (p < 0.05 to p < 0.001) and satiating effects (p < 0.01 to p < 0.001) as (pGlu-Gln)-CCK-8. This confirmed the capability of (pGlu-Gln)-CCK-8[mPEG] to bind to and activate the CCK receptor. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 35 days significantly decreased body weight gain (p < 0.05), food intake (p < 0.01 to p < 0.001) and triacylglycerol deposition in liver (p < 0.001) and muscle (p < 0.001). Furthermore, (pGlu-Gln)-CCK-8[mPEG] markedly improved intraperitoneal glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Despite this therapeutic profile, once daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 33 days, at the same dose, was not associated with alterations in food intake and body weight. In addition, metabolic responses to exogenous glucose and insulin injection were similar to saline treated controls. Conclusion:These studies emphasise the therapeutic potential of (pGlu-Gln)-CCK-8[mPEG] and similar molecules. General significance: A more detailed analysis of the dose and administration schedule employed for (pGlu-Gln)-CCK-8[mPEG] could provide a novel and effective compound to treat obesity-diabetes. (c) 2013 Elsevier B.V. All rights reserved.
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