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Molecular and Cellular Biology, October 2003, p. 7222-7229, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7222-7229.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Elimination of Peroxisome Proliferator-Activated Receptor {gamma} in ß Cells Leads to Abnormalities in Islet Mass without Compromising Glucose Homeostasis

Evan D. Rosen,1* Rohit N. Kulkarni,2 Pasha Sarraf,3,4 Umut Ozcan,2 Terumasa Okada,2 Chung-Hsin Hsu,1 Daniel Eisenman,3,4 Mark A. Magnuson,5 Frank J. Gonzalez,6 C. Ronald Kahn,2 and Bruce M. Spiegelman3,4*

Division of Endocrinology, Beth Israel Deaconess Medical Center,1 Research Division, Joslin Diabetes Center,2 Department of Cell Biology, Harvard Medical School,3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts,4 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee,5 Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland6

Received 15 January 2003/ Returned for modification 2 April 2003/ Accepted 7 July 2003

The nuclear hormone receptor peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is an important regulator of lipid and glucose homeostasis and cellular differentiation. Studies of many cell types in vitro and in vivo have demonstrated that activation of PPAR{gamma} can reduce cellular proliferation. We show here that activation of PPAR{gamma} is sufficient to reduce the proliferation of cultured insulinoma cell lines. We created a model with mice in which the expression of the PPARG gene in ß cells was eliminated (ß{gamma}KO mice), and these mice were found to have significant islet hyperplasia on a chow diet. Interestingly, the normal expansion of ß-cell mass that occurs in control mice in response to high-fat feeding is markedly blunted in these animals. Despite this alteration in ß-cell mass, no effect on glucose homeostasis in ß{gamma}KO mice was noted. Additionally, while thiazolidinediones enhanced insulin secretion from cultured wild-type islets, administration of rosiglitazone to insulin-resistant control and ß{gamma}KO mice revealed that PPAR{gamma} in ß cells is not required for the antidiabetic actions of these compounds. These data demonstrate a critical physiological role for PPAR{gamma} function in ß-cell proliferation and also indicate that the mechanisms controlling ß-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.

* Corresponding author. Mailing address for Evan D. Rosen: Division of Endocrinology, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215. Phone: (617) 667-3221. Fax: (617) 667-2927. E-mail: erosen{at}bidmc.harvard.edu. Mailing address for Bruce M. Spiegelman: Department of Cancer Biology, Dana-Farber Cancer Institute, 1 Jimmy Fund Way, Boston, MA 02115. Phone: (617) 632-3748. Fax: (617) 632-5363. E-mail: bruce_spiegelman{at}dfci.harvard.edu.

Molecular and Cellular Biology, October 2003, p. 7222-7229, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7222-7229.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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