Targeted elimination of peroxisome proliferator-activated receptor γ in β cells leads to abnormalities in islet mass without compromising glucose homeostasis

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