Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival.
An absolute or functional deficit in beta-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven beta-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptin(ob/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 alpha- and beta-cells. We bred a null Cck allele into the C57BL/6-Leptin(ob/ob) background and investigated beta-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced beta-cell mass through increased beta-cell death. CCK deficiency and decreased beta-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect beta-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 beta-cell survival and expand beta-cell mass to compensate for obesity-induced insulin resistance.
Lavine
Jeremy A
JA
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
Raess
Philipp W
PW
Stapleton
Donald S
DS
Rabaglia
Mary E
ME
Suhonen
Joshua I
JI
Schueler
Kathryn L
KL
Koltes
James E
JE
Dawson
John A
JA
Yandell
Brian S
BS
Samuelson
Linda C
LC
Beinfeld
Margery C
MC
Davis
Dawn Belt
DB
Hellerstein
Marc K
MK
Keller
Mark P
MP
Attie
Alan D
AD
D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size / Q000235:genetics; D015854:Up-Regulation
D002766:Cholecystokinin