11月17日,，美國(guó)《國(guó)家科學(xué)院院刊》（PNAS）在線發(fā)表了中國(guó)科學(xué)院上海生命科學(xué)研究院營(yíng)養(yǎng)科學(xué)研究所劉勇研究組和美國(guó)德州大學(xué)達(dá)拉斯西南醫(yī)學(xué)中心的合作研究結(jié)果,，揭示了瘦素受體介導(dǎo)的不同信號(hào)機(jī)制在能量平衡與葡萄糖代謝中的生理學(xué)調(diào)控功能,。
全球處于流行之勢(shì)的肥胖癥是引發(fā)Ⅱ型糖尿病和心血管疾病的重要高危因子,，而人們對(duì)營(yíng)養(yǎng)過剩通過怎樣的生理學(xué)機(jī)制導(dǎo)致肥胖發(fā)生卻所知甚微,。脂肪組織分泌的細(xì)胞因子－瘦素（Leptin）,，通過作用于中樞神經(jīng)下丘腦（Hypothalamus）中特定神經(jīng)元上的瘦素受體（Ob-Rb）激活下游不同的信號(hào)通路,，在能量與糖脂代謝平衡中起著至關(guān)重要的功能,。瘦素抵抗（Leptin resistance－表現(xiàn)為瘦素信號(hào)轉(zhuǎn)導(dǎo)能力的衰損）與肥胖癥,、糖尿病密切相關(guān)，但在生理學(xué)水平上對(duì)瘦素受體傳導(dǎo)的信號(hào)機(jī)制仍舊缺乏全面的認(rèn)知,。因此,，瘦素抵抗發(fā)生的病理學(xué)基礎(chǔ)成為營(yíng)養(yǎng)與代謝研究領(lǐng)域一個(gè)懸而未決的重要問題。
瘦素受體胞內(nèi)端含有三個(gè)關(guān)鍵的酪氨酸（Tyrosine,，Y）位點(diǎn),，其磷酸化能夠激活JAK2-STAT3及ERK等通路，以此控制下游神經(jīng)內(nèi)分泌的信號(hào)功能,，進(jìn)而調(diào)節(jié)能量攝取與能量消耗的平衡以及葡萄糖的代謝,。通過國(guó)際合作，劉勇研究員指導(dǎo)的博士研究生蔣雷,、尤佳等將瘦素受體的胞內(nèi)酪氨酸位點(diǎn)引入點(diǎn)突變,，培育出兩個(gè)品系的瘦素受體基因敲入（Knockin）小鼠模型：一個(gè)品系（Y123F）將985,、1077和1138位的酪氨酸都突變?yōu)楸奖彼幔≒henylalanine, F），而另一個(gè)品系（Y3F）則只將1138位的酪氨酸突變?yōu)楸奖彼?，以此在生理學(xué)水平上探索瘦素受體介導(dǎo)的不同信號(hào)通路在能量代謝中的作用與機(jī)制,。研究結(jié)果表明，985和1077位的酪氨酸主要參與糖代謝的調(diào)節(jié),，而1138位酪氨酸激活的STAT3通路則參與對(duì)飲食,、能量消耗、體溫的調(diào)控,；更為重要的是,，瘦素能夠通過不依賴于酪氨酸介導(dǎo)的信號(hào)機(jī)制，在機(jī)體能量代謝平衡中發(fā)揮多方面的調(diào)節(jié)功能,。這些發(fā)現(xiàn)為闡明瘦素抵抗,、肥胖與糖代謝紊亂發(fā)生的分子基礎(chǔ)提供了重要的生理學(xué)線索。
該項(xiàng)工作得到科技部973研究計(jì)劃,、國(guó)家自然科學(xué)基金委,、上海市科委及中科院等部門的支持，歷時(shí)4年完成,。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS,，doi: 10.1073/pnas.0804589105，Lei Jiang,，Yong Liu
Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis
Lei Jianga,1, Jia Youa,1, Xinxin Yub, Lety Gonzalezb, Yue Yua, Qiong Wanga, Guoqing Yangb,2, Wenjun Lia, Cai Lib,3, and Yong Liua,4
Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Here, we generated 2 knockin lines of mice expressing mutant leptin receptors with phenylalanine substitution for all 3 tyrosines (Y123F) or for Tyr1138 alone (Y3F). Y123F animals developed overt obesity similar to that of Y3F animals with abrogated hypothalamic activation of STAT3 by leptin, but they exhibited more severe impairment in glucose tolerance. In striking contrast to db/db mice, however, both Y123F and Y3F mice showed attenuated adiposity with reduced hyperphagia, marked improvement in physical activity and adaptive thermogenesis, and significantly ameliorated glycemic control. Further, Y123F mice had hypothalamic neuropeptide Y/agouti-related protein expression maintained at prominently lower levels compared with db/db mice. Thus, these results provide direct physiological evidence that Ob-Rb exerts crucial metabolic actions not only through tyrosine-dependent, but also tyrosine-independent mechanisms in control of energy balance and glucose homeostasis.
