Memon R A, Tecott L H, Nonogaki K, Beigneux A, Moser A H, Grunfeld C, Feingold K R
Department of Medicine, University of California, San Francisco 94143, USA.
Endocrinology. 2000 Nov;141(11):4021-31. doi: 10.1210/endo.141.11.7771.
Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. alpha, delta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed. A recent study reported increased PPAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR-gamma expression in the liver has any functional consequences. The expression of PPAR-alpha and -delta in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice. Troglitazone also induced a pronounced increase in the expression of uncoupling protein-2 in the liver in ob/ob mice. In contrast to the liver, troglitazone did not increase the expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice. Taken together, our results suggest that the effects of PPAR-gamma activators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR-gamma in the liver.
过氧化物酶体增殖物激活受体（PPARs）是转录因子，在调节参与脂质利用与储存、脂蛋白代谢、脂肪细胞分化及胰岛素作用的基因方面发挥重要作用。PPAR家族的三种亚型，即α、δ和γ，具有不同的组织分布模式。PPAR-α主要存在于肝脏，PPAR-γ存在于脂肪组织，而PPAR-δ则广泛表达。最近一项研究报道ob/ob小鼠肝脏中PPAR-γ信使核糖核酸（mRNA）表达增加；然而，尚不清楚肝脏中PPAR-γ表达增加是否具有任何功能后果。肥胖时肝脏中PPAR-α和-δ的表达尚未确定。我们现已检测了三种肥胖小鼠模型，即ob/ob（瘦素缺乏）、db/db（瘦素受体缺乏）和血清素5-HT2c受体（5-HT2cR）突变小鼠肝脏中PPAR-α、-δ和-γ的mRNA水平。5-HT2cR突变小鼠发生迟发性肥胖，且与较高的血浆瘦素水平相关。我们的结果显示，在所有三种肥胖模型中，肝脏中PPAR-α mRNA水平增加了2至3倍，而ob/ob和db/db小鼠肝脏中PPAR-γ mRNA水平增加了7至9倍，肥胖的5-HT2cR突变小鼠中增加了2倍。ob/ob或db/db小鼠中PPAR-δ mRNA表达未改变。为确定肝脏中PPAR-γ表达增加是否具有任何功能后果，我们检测了曲格列酮处理对几种PPAR-γ反应性脂肪组织特异性基因肝脏mRNA水平的影响，这些基因在肝脏中要么无检测到的基础表达，要么基础表达非常低。用曲格列酮处理瘦的对照小鼠显著增加了肝脏中脂肪细胞脂肪酸结合蛋白（aP2）和脂肪酸转位酶（FAT/CD36）的表达。曲格列酮诱导的aP2和FAT/CD36表达增加在ob/ob小鼠肝脏中显著增强。曲格列酮还诱导ob/ob小鼠肝脏中解偶联蛋白-2的表达显著增加。与肝脏相反，曲格列酮在瘦或ob/ob小鼠的脂肪组织中未增加aP2、FAT/CD36和解偶联蛋白-2的表达。综上所述，我们的结果表明，PPAR-γ激活剂对肥胖和2型糖尿病中脂质代谢及能量稳态的影响可能部分通过其对肝脏中PPAR-γ的作用介导。
