Pparg-P465L mutation worsens hyperglycemia in Ins2-Akita female mice via adipose-specific insulin resistance and storage dysfunction

OBJECTIVE - The dominant-negative P467L mutation in peroxisome proliferator activated receptor-γ (PPARγ) was identified in insulin-resistant patients with hyperglycemia and lipodystrophy. In contrast, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. We hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, which is masked by hyperinsulinemia and increased pancreatic islet mass, to retain normal plasma glucose. RESEARCH DESIGN AND METHODS - We introduced in Pparg^P465L/+ mice an Ins2-Akita mutation that causes improper protein folding and islet apoptosis to lower plasma insulin. RESULTS - Unlike Ins2^Akita/+ littermates, male Pparg ^P465L/+ Ins2^Akita/+ mice have drastically reduced life span with enhanced type 1 diabetes. Hyperglycemia in Ins2^Akita/+ females is mild. However, PpargP^465L/+ Ins2^Akita/+ females have aggravated hyperglycemia, smaller islets, and reduced plasma insulin. In an insulin tolerance test, they showed smaller reduction in plasma glucose, indicating impaired insulin sensitivity. Although gluconeogenesis is enhanced in Pparg^P465L/+ Ins2^Akita/+ mice compared with Ins2 ^Akita/+, exogenous insulin equally suppressed gluconeogenesis in hepatocytes, suggesting that Pparg^P465L/+ Ins2^Akita/+ livers are insulin sensitive. Expression of genes regulating insulin sensitivity and glycogen and triglyceride contents suggest that skeletal muscles are equally insulin sensitive. In contrast, adipose tissue and isolated adipocytes from Pparg^P465L/+ Ins2^Akita/+ mice have impaired glucose uptake in response to exogenous insulin. Pparg^P465L/+ Ins2 ^Akita/+ mice have smaller fat depots composed of larger adipocytes, suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia. CONCLUSIONS - PPARg-P465L mutation worsens hyperglycemia in Ins2^Akita/+ mice primarily because of adipose-specific insulin resistance and altered storage function. This underscores the important interplay between insulin and PPARγ in adipose tissues in diabetes.