Tsai Yau-Sheng, Kim Hyo-Jeong, Takahashi Nobuyuki, Kim Hyung-Suk, Hagaman John R, Kim Jason K, Maeda Nobuyo
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Clin Invest. 2004 Jul;114(2):240-9. doi: 10.1172/JCI20964.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）是一类胰岛素增敏剂的分子靶点，可调节脂肪细胞分化和脂质代谢。人类PPARγ配体结合域中的显性负性P467L突变与严重胰岛素抵抗和高血压相关。具有等效P465L突变的纯合小鼠在子宫内死亡。杂合小鼠生长正常，总脂肪组织重量正常。然而，与野生型小鼠相比，它们肩胛间棕色脂肪组织和腹腔内脂肪量减少，腹部外皮下脂肪增加。它们的血糖水平和胰岛素敏感性正常，葡萄糖耐量增加。然而，在高脂喂养期间，它们的血浆胰岛素水平轻度升高，同时胰岛质量显著增加。它们患有高血压，皮下脂肪组织中血管紧张素原基因的表达增加。无论饮食和年龄如何，P465L对雄性和雌性小鼠的血压、脂肪分布和胰岛素敏感性的影响都是相同的。因此，单独的P465L突变足以导致小鼠脂肪分布异常和高血压，但不会导致胰岛素抵抗。这些结果为PPARγ在血压调节中不依赖于胰岛素敏感性改变的关键作用提供了遗传学证据。
