Yoshino Satoshi, Satoh Tetsurou, Yamada Masanobu, Hashimoto Koshi, Tomaru Takuya, Katano-Toki Akiko, Kakizaki Satoru, Okada Shuichi, Shimizu Hiroyuki, Ozawa Atsushi, Tuchiya Takafumi, Ikota Hayato, Nakazato Yoichi, Mori Munemasa, Matozaki Takashi, Sasaki Tsutomu, Kitamura Tadahiro, Mori Masatomo
Departments of Medicine and Molecular Science (S.Y., T.Sat., M.Y., K.H., T.To., A.K.-T., S.K., S.O., H.S., A.O., T.Tu., Ma.Mori) and Human Pathology (H.I., Y.N.), Gunma University Graduate School of Medicine, Maebashi, 371-8511 Japan; Laboratory of Biosignal Sciences (Mu.Mori, T.Ma.) and Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation (T.Sas., T.K.), Gunma University, Maebashi, 371-8512 Japan; and Kitakanto Molecular Novel Research Institute for Obesity and Metabolism (Ma.Mori), Midori, 379-2311 Japan.
Endocrinology. 2014 Sep;155(9):3459-72. doi: 10.1210/en.2013-2160. Epub 2014 Jul 8.
Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.
肥胖源于能量平衡受损，而能量平衡由瘦素通过激活长型瘦素受体（Leprb）进行中枢协调。肥胖会导致中枢性瘦素抵抗。然而，增强外周瘦素敏感性是否能克服中枢性瘦素抵抗仍不清楚。肝脏是瘦素作用的外周代谢器官，其Leprb表达较低。我们在此表明，喂食高脂饮食（HFD）的小鼠和患有肝脂肪变性的肥胖患者肝脏中具有锌指结构的解旋酶2（一种转录共激活因子，Helz2）的表达增加，Helz2在体外作为包括过氧化物酶体增殖物激活受体γ在内的几种核受体的转录共调节因子发挥作用。为了探究Helz2的生理重要性，我们构建了Helz2基因缺失小鼠并分析其代谢表型。Helz2基因缺失小鼠表现出与中枢性瘦素抵抗相关的高瘦素血症，但能抵抗HFD诱导的肥胖，且肝脏Leprb表达显著上调。Helz2基因缺失以及在野生型小鼠中通过腺病毒介导肝脏特异性外源性Leprb过表达，在HFD喂养时可显著刺激肝脏中的AMP激活蛋白激酶，而缺乏功能性Leprb的Helz2基因缺失db/db小鼠则无此现象。Helz2基因缺失的肝细胞中脂肪酸β氧化增加，在热量测定分析中，Helz2基因缺失小鼠显示耗氧量增加，呼吸商降低。Helz2基因缺失小鼠中增强的肝脏AMP激活蛋白激酶能量感应途径通过降低肝脏中脂肪生成基因的表达并刺激脂肪燃烧基因的表达，改善了高脂血症、肝脂肪变性和胰岛素抵抗。这些发现共同表明，尽管存在中枢性瘦素抵抗，但Helz2基因缺失通过刺激内源性肝脏Leprb表达改善了HFD诱导的代谢异常。肝脏中的HELZ2可能是治疗伴有肝脂肪变性的肥胖症的新型靶分子。
