Targeted Elimination of Peroxisome Proliferator-Activated Receptor γ in β Cells Leads to Abnormalities in Islet Mass without Compromising Glucose Homeostasis

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ can reduce cellular proliferation. We show here that activation of PPARγ 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 β cells was eliminated (βγKO mice), and these mice were found to have significant islet hyperplasia on a chow diet. Interestingly, the normal expansion of β-cell mass that occurs in control mice in response to high-fat feeding is markedly blunted in these animals. Despite this alteration in β-cell mass, no effect on glucose homeostasis in βγKO mice was noted. Additionally, while thiazolidinediones enhanced insulin secretion from cultured wild-type islets, administration of rosiglitazone to insulin-resistant control and βγKO mice revealed that PPARγ in β cells is not required for the antidiabetic actions of these compounds. These data demonstrate a critical physiological role for PPARγ function in β-cell proliferation and also indicate that the mechanisms controlling β-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.

ACKNOWLEDGMENTS

We thank K. C. Hayes and the staff of the animal facility of the Foster Biomedical Laboratories at Brandeis University.

This work was supported by NIH grants KO8 DK02535 (to E.D.R.), RO3 DK58850 (to E.D.R.), R37DK31405 (to B.M.S.), RO1 DK33201 (to C.R.K.), and KO8 DK02885 (to R.N.K.).