Hypertension and abnormal fat distribution but not insulin resistance in mice
with P465L PPARgamma.
Authors Tsai YS, Kim HJ, Takahashi N, Kim HS, Hagaman JR, Kim JK, Maeda N
Submitted By Nobuyo Maeda on 11/12/2007
Status Published
Journal The Journal of clinical investigation
Year 2004
Date Published 7/1/2004
Volume : Pages 114 : 240 - 249
PubMed Reference 15254591
Abstract Peroxisome proliferator-activated receptor gamma (PPARgamma), the molecular
target of a class of insulin sensitizers, regulates adipocyte differentiation
and lipid metabolism. A dominant negative P467L mutation in the ligand-binding
domain of PPARgamma in humans is associated with severe insulin resistance and
hypertension. Homozygous mice with the equivalent P465L mutation die in utero.
Heterozygous mice grow normally and have normal total adipose tissue weight.
However, they have reduced interscapular brown adipose tissue and
intra-abdominal fat mass, and increased extra-abdominal subcutaneous fat,
compared with wild-type mice. They have normal plasma glucose levels and insulin
sensitivity, and increased glucose tolerance. However, during high-fat feeding,
their plasma insulin levels are mildly elevated in association with a
significant increase in pancreatic islet mass. They are hypertensive, and
expression of the angiotensinogen gene is increased in their subcutaneous
adipose tissues. The effects of P465L on blood pressure, fat distribution, and
insulin sensitivity are the same in both male and female mice regardless of diet
and age. Thus the P465L mutation alone is sufficient to cause abnormal fat
distribution and hypertension but not insulin resistance in mice. These results
provide genetic evidence for a critical role for PPARgamma in blood pressure
regulation that is not dependent on altered insulin sensitivity.

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina