NEW YORK (Reuters Health) - PPAR-gamma appears to play a critical role in blood pressure regulation that is independent of its role in altered insulin sensitivity, according to a report in the July 15th issue of The Journal of Clinical Investigation.
P467 mutations in the ligand-binding domain of peroxisome proliferator-activated receptor (PPAR)-gamma are associated with severe insulin resistance and hypertension in humans, the authors explain, but how these mutations cause these clinical findings is not known.
Dr. Nobuyo Maeda from University of North Carolina, Chapel Hill, and colleagues bred mice to have analogous mutations to determine whether the P467L mutation seen in humans directly causes insulin resistance and hypertension.
Mice bearing the equivalent P465L mutation (P465L mice) had normal metabolic and histological parameters, the authors report, but showed abnormal body fat distribution, with preferential deposition in subcutaneous fat pads rather than in intra-abdominal fat pads.
P465L mice showed normal insulin sensitivity, the report indicates, but mean tail cuff blood pressure was significantly higher (p < 0.01) in mutated mice than in wild-type mice.
The systemic renin-angiotensin system (RAS) was not altered in P465L PPAR-gamma-mediated hypertension, the researchers note. Rather, the genes of the RAS were selectively altered in adipose tissue of mutated mice in a depot-specific fashion.
“These data suggest that the elevated blood pressure of [mutated] mice could be affected by changes in the local RAS of adipose tissues,” the investigators write.
“Our [P465L] mice provide genetic evidence for an important link between PPAR-gamma and the regulation of blood pressure and fat distribution that is independent of any alteration in insulin sensitivity,” the authors conclude.
“These similarities and differences in the phenotypes caused by an identical mutation in two species provide an opportunity to further dissect the role of PPAR-gamma in the pathogenesis of the metabolic syndrome.”
“The findings in the [P465L] mice further weaken the case for direct links among adipose redistribution, insulin resistance, and hypertension,” write Dr. Robert A. Hegele from Robarts Research Institute, London, Ontario, Canada and Dr. Todd Leff from Wayne State University School of Medicine, Detroit, Michigan in a related commentary.
These data also “reinforce the importance of PPAR-gamma in adipogenesis, highlight the role of adipose tissue as an endocrine organ, and also support the idea that PPARG mutations affect metabolic and vascular phenotypes through multiple mechanisms, some of which are distinct from effects on adipose tissue mass or distribution.”
Source: J Clin Invest 2004;114:163-165,240-249. [ Google search on this article ]
MeSH Headings:Animal Diseases: Carbohydrate Metabolism, Inborn Errors: Disease Models, Animal: Glucose Intolerance: Peroxisomes: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
