Aims/hypothesis Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. Methods The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. Results (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p<0.05 to p<0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p<0.01 to p<0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p<0.05 to p<0.001), accumulated food intake (p< 0.05 to p<0.001), non-fasting glucose (p<0.05) and triacylglycerol deposition in pancreatic (p<0.01), adipose (p< 0.05) and liver (p<0.001) tissue, and improved oral (p< 0.05) and i.p. (p<0.05) glucose tolerance and insulin sensitivity (p<0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. Conclusions/interpretation These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

This study highlights the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.

These results suggest that immunoneutralization of GIP represents an effective means of countering the disruption of metabolic processes induced by high-fat feeding.

These studies highlight the potential of (pGlu-Gln)-CCK-8 and (Pro(3))GIP[mPEG] in the treatment of obesity-related diabetes, but there was no evidence of a synergistic effect of the combined treatment.

loss and improves both insulin resistance and glucose tolerance in mouse models of obesitydiabetes [ 3 , 4 ] . Despite the therapeutic potential for (pGlu-Gln)-CCK-8, there is a lack of information on its central eff ects. Therefore, the current study examined the consequence of twice daily (pGlu-Gln)-CCK-8 administration on metabolic status and the expression of key hypothalamic genes involved in energy balance in high fat mice. Materials and Methods ▼ Peptides(pGlu-Gln)-CCK-8 was obtained from American peptide company (Sunnyvale, USA) and characterized as described previously [ 3 ] . AnimalsMale Swiss NIH mice (Harlan UK Ltd.; 10-12 weeks) had free access to drinking water and standard rodent maintenance (10 % fat, 30 % protein and 60 % carbohydrate, Trouw Nutrition, Cheshire, UK) or high fat (45 % fat, 35 % carbohydrate and 20 % protein, Special Diet Services, UK)