Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-γ-deficient mice on a high-fat diet

Abstract

Heterozygous peroxisome proliferator-activated receptor-γ (PPAR-γ)-deficient (PPARγ+/-) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-γ activity on β-cell function, we investigated insulin secretion in PPARγ+/- mice on a high-fat diet. Glucose-induced insulin secretion in PPARγ+/- mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARγ+/- mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-γ+/- agonist, pioglitazone, reduced the islet TG content in PPARγ+/- mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-γ protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-γ agonist can restore impaired insulin secretion under conditions of islet fat accumulation.