Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival

Jeremy A. Lavine, Phil Raess, Donald S. Stapleton, Mary E. Rabaglia, Joshua I. Suhonen, Kathryn L. Schueler, James E. Koltes, John A. Dawson, Brian S. Yandell, Linda C. Samuelson, Margery C. Beinfeld, Dawn Belt Davis, Marc K. Hellerstein, Mark P. Keller, Alan D. Attie

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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)wasthe most up-regulatedgenein 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.

Original languageEnglish (US)
Pages (from-to)3577-3588
Number of pages12
JournalEndocrinology
Volume151
Issue number8
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

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Obese Mice
Cholecystokinin
Islets of Langerhans
Cell Survival
Obesity
Cell Death
Endoplasmic Reticulum Stress
Hyperinsulinism
Cell Size
Hyperglycemia
Insulin Resistance
Fasting
Cell Culture Techniques
Alleles
Cytokines

ASJC Scopus subject areas

  • Endocrinology

Cite this

Lavine, J. A., Raess, P., Stapleton, D. S., Rabaglia, M. E., Suhonen, J. I., Schueler, K. L., ... Attie, A. D. (2010). Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival. Endocrinology, 151(8), 3577-3588. https://doi.org/10.1210/en.2010-0233

Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival. / Lavine, Jeremy A.; Raess, Phil; 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.; Belt Davis, Dawn; Hellerstein, Marc K.; Keller, Mark P.; Attie, Alan D.

In: Endocrinology, Vol. 151, No. 8, 01.08.2010, p. 3577-3588.

Research output: Contribution to journalArticle

Lavine, JA, Raess, P, Stapleton, DS, Rabaglia, ME, Suhonen, JI, Schueler, KL, Koltes, JE, Dawson, JA, Yandell, BS, Samuelson, LC, Beinfeld, MC, Belt Davis, D, Hellerstein, MK, Keller, MP & Attie, AD 2010, 'Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival', Endocrinology, vol. 151, no. 8, pp. 3577-3588. https://doi.org/10.1210/en.2010-0233
Lavine, Jeremy A. ; Raess, Phil ; 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. ; Belt Davis, Dawn ; Hellerstein, Marc K. ; Keller, Mark P. ; Attie, Alan D. / Cholecystokinin is up-regulated in obese mouse islets and expands β-cell mass by increasing β-cell survival. In: Endocrinology. 2010 ; Vol. 151, No. 8. pp. 3577-3588.
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