Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma. Journal   The Journal of clinical investigation. Citation   J Clin Invest. 114(2):240-9 Publication date   2004 Jul Authors   Tsai YS Kim HJ Takahashi N Kim HS Hagaman JR Kim JK Maeda N Investigators   Jason K. Kim Grant agencies   National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute Grants   NIDDK DK 59635 NHLBI HL42630 NHLBI HL70523 MeSH headings   Adipose Tissue Blood Pressure Hypertension Insulin Resistance Mutation, Missense Receptors, Cytoplasmic and Nuclear Transcription Factors MeSH qualifiers   anatomy & histology physiology metabolism 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.