Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes

Pathak, Varun; Flatt, Peter; Irwin, Nigel

doi:10.1016/j.peptides.2017.09.007

Cited by 56 publications

(46 citation statements)

References 71 publications

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“…CCK may also play a role in other regulated insulin secretion, such as amino acid-stimulated insulin secretion 44 or the enhancement of GSIS by GLP-1 45 . These beneficial effects, along with the impact of CCK on β-cell survival 4,5,46 , still make CCK a strong therapeutic candidate with the potential to treat obesity and type 2 diabetes 47 .…”

Section: Discussionmentioning

confidence: 99%

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Souza

Tang

Yadev

et al. 2020

Sci Rep

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Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic β-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to β-cell signaling through the β-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human β-cell function.The precise control of blood glucose is dependent on the islets of Langerhans located within the pancreas. Pancreatic islets are complex structures consisting of several types of cells, including insulin-producing β-cells, glucagon-producing α-cells, and somatostatin-producing α-cells. After feeding, nutrients stimulate insulin release by the β-cell and the circulating hormone acts on peripheral tissues lowering blood glucose. The full stimulation of insulin secretion after food intake depends on the incretin effect of gut-derived peptide hormones and paracrine signaling within the islet 1 .We and others discovered that two classic gut hormones, glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), are also produced by pancreatic islets 2-5 . GLP-1 is a peptide hormone mainly secreted by intestinal L-cells and is known to decrease blood glucose levels by enhancing β-cell insulin secretion 6 . CCK is a peptide hormone mainly secreted by intestinal I-cells and is involved in the digestion of nutrients 7 and regulation of food intake 8 . The production of both GLP-1 and CCK in the islet has been associated with β-cell expansion and survival in response to metabolic stress 5,9 . While each of these gut-derived hormones can contribute to improvements in glucose homeostasis 10,11 , it is unclear whether their local production in the islet contributes to β-cell function. Moreover, it is unknown whether CCK stimulates insulin release in human islets. Here, we describe experiments with GLP-1 and CCK receptor antagonists in isolated mouse and human islets to ass...

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Section: Discussionmentioning

confidence: 99%

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Souza

Tang

Yadev

et al. 2020

Sci Rep

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“…Taking into account (a) the role of CCK in regulating WAT homeostasis (Plaza, Merino, Cano, et al, ), (b) the existence of a complete CCK system in WAT (Plaza, Merino, Sánchez‐Pernaute, et al, ), and (c) the already reported interaction between CCK and insulin in driving energy metabolism (Irwin et al, ; Irwin et al, ; Pathak, Flatt, & Irwin, ), we aimed at investigating the effect of the C‐terminal bioactive fragment of CCK, CCK‐8, on both adiponectin gene ( Adipoq ) expression and adiponectin production in rat WAT.…”

Section: Introductionmentioning

confidence: 99%

The cholecystokinin receptor agonist, CCK‐8, induces adiponectin production in rat white adipose tissue

Plaza

Merino

Olmo

et al. 2019

British J Pharmacology

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Background and Purpose:A cholecystokinin (CCK) system has been identified in white adipose tissue (WAT). Nevertheless, the endocrine actions of CCK on WAT remain unknown. Our goal was to investigate the role of CCK in regulating the production of adiponectin, an adipokine expressed in WAT, which is pivotal in preserving energy homeostasis. Experimental Approach:The effect of the bioactive CCK fragment CCK-8 on adiponectin production was studied both in vivo and in vitro. CCK-8 effects were characterized in rats treated with selective CCK 1 and CCK 2 receptor antagonists as well as in pre-adipocytes carrying the selective silencing of either CCK 1 or CCK 2 receptors. The influence of insulin on CCK-8 responses was also analysed. Key Results: In WAT, CCK-8 increased plasma adiponectin levels and the expression of the adiponectin gene (Adipoq). In pre-adipocytes, CCK-8 up-regulated adiponectin production. CCK-8 effects were abolished by L-365,260, a selective CCK 2 receptor antagonist. CCK 2 receptor knockdown also abolished the effects of CCK-8 in pre-adipocytes. Moreover, in vitro CCK-8 effects were blocked by triciribine, a specific inhibitor of protein kinase B (Akt) and by the PPARγ antagonist T0070907. Silencing the expression of the insulin receptor inhibited CCK-8-induced Adipoq expression in pre-adipocytes. Furthermore, insulin potentiated the effect of CCK-8. Conclusion and Implications: CCK-8 stimulates adiponectin production in WAT by acting on CCK 2 receptors, through a mechanism involving both Akt and PPARγ. Moreover, CCK-8 actions are only observed in the presence of insulin. Our results could have translational value in the design of new insulin-sensitizing therapies.

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“…Obesity is one of the major challenges for public health in the world, and the prevalence of obesity has augmented dramatically in recent years ( Dirinck et al, 2011 ; Flegal et al, 2012 ). According to the World Health Organization (WHO) reports, the number of obesity people has quadrupled in the last three decades ( Mishra et al, 2016 ; Pathak et al, 2018 ). Obesity is the root reason of metabolic syndrome and chronic diseases, such as type 2 diabetes, hypertension and cardiovascular diseases ( Haslam and James, 2005 ; Eckel et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

The Protective Effects of Danggui-Baizhu-Tang on High-Fat Diet-Induced Obesity in Mice by Activating Thermogenesis

et al. 2018

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Danggui-Baizhu-Tang (DBT), a traditional Chinese medicine decoction, was used for decreasing serum TG and TC remarkably. However, effect of weight control and action mechanism remains confused. In this study, to evaluate the anti-obesity effects, different gradient concentration of DBT (0.59, 1.17 g/kg) or Orlistat (Orl, 15.6 mg/kg; positive control) were administrated by gavage for 8 weeks in C57BL/6J mice which were pretreated with chow or high fat diet (HFD) for 3 months. After administration, significant decrease of body weight and food utilization was observed. It was indicated that concentration of triacylglycerol (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum were reduced strikingly, as well as accumulation of lipid droplets in liver. Meanwhile, DBT treatment could also decrease weight of white adipose tissue (WAT) and size of adipocytes, whereas increase weight of brown adipose tissue (BAT) in mice. Moreover, it was revealed that DBT could elevate rectal temperature by raising expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), which were attributed to phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, TNF-α and IL-6, obesity-related inflammatory cytokines, were decreased. In conclusion, DBT could stimulate phosphorylation of AMPK to raise expression of UCP1 and PGC-1α, and activate thermogenesis to prevent obesity.

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Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes

Cited by 56 publications

References 71 publications

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

The cholecystokinin receptor agonist, CCK‐8, induces adiponectin production in rat white adipose tissue

The Protective Effects of Danggui-Baizhu-Tang on High-Fat Diet-Induced Obesity in Mice by Activating Thermogenesis

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