Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

Abstract

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.

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

“…Nonetheless, in harmony with previous observations [7], sub-chronic administration of (pGlu-Gln)-CCK-8 twice daily to high-fat-fed mice resulted in a marked improvement in metabolic status, glucose homeostasis and insulin sensitivity, indicative of the increased metabolic efficiency that typically accompanies weight loss. Importantly, we have previously shown that (pGlu-Gln)-CCK-8 does not affect insulin sensitivity when administered acutely to mice [7]. Decreased energy intake was also observed together with decreases in body weight gain, circulating insulin and triacylglycerol levels, as well as reduced accumulation of tissue triacylglycerol.…”

“…), and not i.p., peptide administration [18]. Nonetheless, in harmony with previous observations [7], sub-chronic administration of (pGlu-Gln)-CCK-8 twice daily to high-fat-fed mice resulted in a marked improvement in metabolic status, glucose homeostasis and insulin sensitivity, indicative of the increased metabolic efficiency that typically accompanies weight loss. Importantly, we have previously shown that (pGlu-Gln)-CCK-8 does not affect insulin sensitivity when administered acutely to mice [7].…”

“…In this regard, structurefunction analysis has shown that the amino acid sequences of CCK and leptin can be dissociated into distinct shorter fragments that still retain biological actions of the parent peptides [7,12]. Thus, development of shorter bioactive forms of CCK and leptin might reduce production costs and facilitate non-injectable drug delivery, thereby increasing their overall utility.…”

“…Therefore, the present study has evaluated the bioactivity and possible therapeutic potential of fragment CCK and leptin peptides, namely (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3. We and others have recently highlighted the involvement of CCK receptor signalling in insulin secretion and for controlling glucose homeostasis both in normal rodents and in animal models with established obesity/diabetes [7,28]. However, leptin is generally considered to inhibit insulin secretion [29].…”

“…There are a number of molecular isoforms of CCK ranging from 58 to four amino acids in length, but CCK-8 is the smallest form that retains the full range of biological actions [6]. Thus, we have developed (pGlu-Gln)-CCK-8, an enzymatically stable CCK-8 analogue, and shown that sub-chronic twice daily administration of this peptide can reverse many of the established metabolic abnormalities associated with obesity/diabetes [7].…”