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

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 (pGluGln)-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), nonfasting 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/interpretationThese 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.

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

“…However, assessment of pancreatic cell volumes would be required to fully confirm islet proliferative effects of the treatment regimens. Furthermore, notable reductions in total and LDL-cholesterol concentrations were observed with all treatment regimens, in agreement with effects of individual peptides in previous studies (5,(9)(10)(11). HDL-cholesterol concentrations also were reduced by the hybrid, which was unique to this treatment modality and necessitates further investigation.…”

Two novel glucagon receptor antagonists prove effective therapeutic agents in high‐fat‐fed and obese diabetic mice

“…Consistent with previous reports , normal mice fed a high fat (45%) diet show substantial impairments in metabolic status. This includes hyperglycaemia and hyperinsulinaemia, with notable impairments of glucose tolerance and insulin sensitivity and elevated cholesterol levels.…”

Ghrelin, CCK, GLP-1, and PYY(3–36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB

“…First, stabilized forms of CCK that resist enzymatic degradation reduced food intake and body weight in various mouse obesity models (357,359,582). Second, native and stabilized CCK and CCKAR agonists increased the anorectic and weight-lowering actions of a GLP-1 receptor agonist, amylin, leptin, or amylin plus leptin in various rat and mouse obesity models (358,776,777), as did a CCK/GLP-1 agonist hybrid peptide (360). These promising results suggest that increased CCK signaling may contribute effectively to obesity pharmacotherapy.…”