Peroxisome proliferator receptor gamma and the control of glucose metabolism: insights from knockout mice

Abstract

Peroxisome proliferator receptor gamma (PPARγ) is a nuclear receptor first identified for its role in adipose tissue differentiation. Two PPARγ isoforms were identified that differed at the amino terminus with the PPARγ2 isoform having an amino-terminal extension. The whole-body deletion of all PPARγ isoforms causes embryonic lethality due to a defect in placental vascularization, so other genetic approaches have been used to study its role in development and metabolism. Mice heterozygous for global PPARγ deletion were viable however and were protected from high-fat diet-induced insulin resistance. Whole-body deletion of the longer PPARγ2 isoform caused insulin resistance even for mice on a regular diet. PPARγ is highly expressed in adipose tissue, so it was deleted in this tissue to study its involvement in glucose homeostasis and insulin resistance. These studies showed that PPARγ is required for adipocyte survival and its loss caused lipodystrophy. Deletion in macrophages predisposed mice to diet-induced obesity and insulin resistance. When deleted in either the liver or skeletal muscle, animals were prone to glucose intolerance and insulin resistance. Interestingly, deletion in neurons had no effect on glucose homeostasis, although animals were protected from obesity-induced leptin resistance. In contrast, astrocyte-specific knockout mice had impaired glucose tolerance and hepatic steatosis that did not worsen with HFD. The studies reviewed here show that PPARγ acts in many tissues, not only adipose tissue, to regulate glucose metabolism.