Analyses of the peroxisome proliferator-activated receptor gamma

• Main Author: Browne, P. O.
• Published: University of Cambridge 2001
• Subjects: 572
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597020

The peroxisome proliferator-activated receptor γ(PPARγ) plays a key role in the development of adipose tissue, and over the last few years has attracted increasing attention as the most likely target for a new and potent class for anti-diabetic drugs known as the thiazolidinediones (TZDs). The first part of this work investigated whether mutations in the gene encoding PPARγ are responsible for syndromes of aberrant adipose tissue development. The entire coding sequence of the PPARγ gene was screened in 9 individuals with inherited forms of lipodystrophy, and 98 children affected by severe early onset obesity were screened for activating mutations within the second exon of the PPARγ gene. Neither study identified any mutations that might contribute to these syndromes. The second part of this work investigated whether a common mutation in the amino-terminus of PPAR-γ (PPARγ Pro12A1a) was associated with body mass index (BMI) and/or insulin sensitivity in a UK Caucasian population. The results of this study suggest that there is a diet-dependent association of the PPARγ2 Prol2A1a mutation with BMI and as a consequence of this with insulin sensitivity. The final part of this work concerned the evaluation of an artificial dominant negative PPARγ mutant (PPARγ<SUB>m</SUB>), and the generation of transgenic mouse lines in which PPARγ activity is blocked in skeletal muscle and adipose tissue by tissue specific expression of PPARγ<SUB>m</SUB>. I hope that these transgenic will enable us to prove conclusively whether or not PPARγ is the mediator of insulin sensitisation by the TZDs.