Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARγ
Yau-Sheng Tsai, … , Jason K. Kim, Nobuyo Maeda
Yau-Sheng Tsai, … , Jason K. Kim, Nobuyo Maeda
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):240-249. https://doi.org/10.1172/JCI20964.
View: Text | PDF
Article Cardiology Article has an altmetric score of 3

Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARγ

Abstract

Peroxisome proliferator–activated receptor γ (PPARγ), 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 PPARγ 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 PPARγ in blood pressure regulation that is not dependent on altered insulin sensitivity.

Authors

Yau-Sheng Tsai, Hyo-Jeong Kim, Nobuyuki Takahashi, Hyung-Suk Kim, John R. Hagaman, Jason K. Kim, Nobuyo Maeda

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Generation of mice with the PPARγ P465L mutation. (A) Crossovers (indica...
Generation of mice with the PPARγ P465L mutation. (A) Crossovers (indicated by the large X marks) between the wild-type mouse Pparg locus with Pro465 in exon 6 (6P) (top diagram) and targeting construct with Leu465 (6L) (second diagram) resulted in the targeted allele in ES cells (third diagram). The ACN (Cre-Neo) cassette, flanked by loxP sequences, was excised out of the mutant allele upon germline transmission (bottom diagram). B, X, Xb, and St indicate the BamHI, XhoI, XbaI, and StuI restriction enzyme sites, respectively. tAce, testis-specific Ace promoter; TK, thymidine kinase. (B) Southern blot analysis of genomic DNA. The targeted allele was identified by a 5′ probe that hybridizes to an 11-kb fragment in wild-type (+/+) DNA and to a 7.7-kb fragment in heterozygous DNA that includes the P465L mutation (L/+). (C) PPARγ mRNA of the wild-type (white bars) and mutant allele (black bar) in gonadal adipose tissue from wild-type and PpargP465L/+ mice (n = 8 each). The PPARγ mRNA amount is expressed relative to that of wild-type allele in wild-type mice. (D) Rosiglitazone-induced PEPCK expression in gonadal adipose tissue explants. Tissues isolated from four wild-type (open squares) and four PpargP465L/+ (filled squares) mice were incubated in cultured media containing various concentrations of PPARγ agonist rosiglitazone as indicated. The levels of PEPCK mRNA are relative to the wild-type basal level. *P < 0.01 and **P < 0.005 compared with the respective basal levels.