Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands β-Cell Mass by Increasing β-Cell Survival

• Published in: Endocrinology (Philadelphia) Vol. 151; no. 8; pp. 3577 - 3588
• Main Authors: Lavine, Jeremy A, Raess, Philipp W, Stapleton, Donald S, Rabaglia, Mary E, Suhonen, Joshua I, Schueler, Kathryn L, Koltes, James E, Dawson, John A, Yandell, Brian S, Samuelson, Linda C, Beinfeld, Margery C, Davis, Dawn Belt, Hellerstein, Marc K, Keller, Mark P, Attie, Alan D
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.08.2010; The Endocrine Society
• Subjects: Animals; Cell Count; Cell Survival - genetics; Cells, Cultured; Cholecystokinin - genetics; Cholecystokinin - metabolism; Diabetes Mellitus - etiology; Diabetes Mellitus - genetics; Insulin Resistance - genetics; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity - complications; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Organ Size - genetics; Up-Regulation
• DOI: 10.1210/en.2010-0233
• ISSN: 0013-7227

An absolute or functional deficit in β-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven β-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptinob/ob mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both α- and β-cells. We bred a null Cck allele into the C57BL/6-Leptinob/ob background and investigated β-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced β-cell mass through increased β-cell death. CCK deficiency and decreased β-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect β-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase β-cell survival and expand β-cell mass to compensate for obesity-induced insulin resistance. Cholecystokinin is up-regulated in the islet by obesity. Islet CCK expression prevents obesity-induced hyperglycemia by increasing β-cell survival and expanding β-cell mass.