Peroxisome proliferator-activated receptor γ—insights from human genetics

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ), mediates adipocyte differentiation and is the target for the thiazolidinedione (TZD) group of insulin-sensitising antidiabetic agents. We screened the PPARγ gene in 85 subjects with severe insulin resistance and identified heterozygous, missense mutations in several individuals from different families. Functional studies indicate that the receptor mutants are transcriptionally impaired and inhibit wild-type PPARγ action in a dominant negative manner. The clinical phenotype also includes partial lipodystrophy, dyslipidaemia, hepatic steatosis and early onset hypertension. Diminished fat mass, reduced circulating adiponectin and impaired lipid flux in adipose tissue contribute to severe insulin resistance. Responses to TZD treatment in two subjects mirrored the properties of their mutant receptors in vitro. In a large kindred with five individuals with severe insulin resistance, we have identified frameshift/premature stop mutations in PPARγ and muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A) genes. This PPARγ stop mutant exhibits complete loss of function with no dominant negative activity; the PPP1R3A truncation mutant is mislocalised intracellularly. Individuals harbouring either gene defect alone have normal insulin levels, but double heterozygosity for the gene defects co-segregates with severe insulin resistance. This kindred represents the first description of a digenic basis for insulin resistance and suggests that a metabolic dialogue between adipose tissue and skeletal muscle regulates insulin action.