Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets

Peroxisome proliferator-activated receptor (PPAR) alpha is a transcription factor controlling lipid and glucose homeostasis. PPAR alpha-deficient (-/-) mice are protected from high-fat diet-induced insulin resistance. However, the impact of PPAR alpha in the pathophysiological setting of obesity-related insulin resistance is unknown. Therefore, PPAR alpha(-/-) mice in an obese (ob/ob) background were generated. PPAR alpha deficiency did not influence the growth curves of the obese mice but surprisingly resulted in a severe, age-dependent hyperglycemia. PPAR alpha deficiency did not aggravate peripheral insulin resistance. By contrast, PPAR alpha(-/-) ob/ob mice developed pancreatic beta-cell dysfunction characterized by reduced mean islet area and decreased insulin secretion in response to glucose in vitro and in vivo. In primary human pancreatic islets, PPAR alpha agonist treatment prevented fatty acid-induced impairment of glucose-stimulated insulin secretion, apoptosis, and triglyceride accumulation. These results indicate that PPAR alpha improves the adaptative response of the pancreatic beta-cell to pathological conditions. PPAR alpha could thus represent a promising target in the prevention of type 2 diabetes.