Al Rayyan Numan, Zhang Jinhua, Burnside Amy S, Good Deborah J
Department of Human Nutrition, Foods and Exercise, 1981 Kraft Drive, ILSB Room 1020 (0913), Virginia Tech, Blacksburg, VA 24061, United States.
Department of Veterinary and Animal Sciences, Integrated Sciences Building, University of Massachusetts, 661 N. Pleasant Street, Amherst, MA 01003, United States.
Mol Cell Endocrinol. 2014 Mar 25;384(1-2):134-42. doi: 10.1016/j.mce.2014.01.017. Epub 2014 Jan 29.
Mice with a deletion of the hypothalamic basic helix-loop-helix transcription factor Nhlh2 display adult onset obesity. We have previously shown that Nhlh2 expression is induced by leptin. In this study, we identify a small proximal leptin-responsive promoter region in the Nhlh2 gene. This 163bp promoter contains five putative binding sites for the leptin-activated Stat3 transcription factor, and two putative binding sites for the NFκB transcription factor. Results of mutagenesis studies reveal that deletion of the NFκB sites have little effect, mutagenesis of the third Stat3 site eliminates both leptin-induced and basal expression of Nhlh2. Mutagenesis of the 4th and 5th sites eliminates leptin-induced expression, and increases basal expression above the WT promoter. Stat3 can be preferentially pulled down from leptin-treated mouse hypothalamic chromatin extracts. This study identifies leptin-induced Stat3 transcription factor as the major transcriptional regulator of Nhlh2. As Nhlh2 transcriptionally regulates genes within the melanocortin pathway, these findings have implications for human body weight control.
下丘脑碱性螺旋-环-螺旋转录因子Nhlh2缺失的小鼠表现出成年后肥胖。我们之前已表明Nhlh2的表达由瘦素诱导。在本研究中，我们在Nhlh2基因中鉴定出一个小的近端瘦素反应性启动子区域。这个163bp的启动子包含五个瘦素激活的Stat3转录因子的假定结合位点，以及两个NFκB转录因子的假定结合位点。诱变研究结果显示，NFκB位点的缺失影响很小，第三个Stat3位点的诱变消除了瘦素诱导的和Nhlh2的基础表达。第4和第5位点的诱变消除了瘦素诱导的表达，并使基础表达高于野生型启动子。Stat3可从瘦素处理的小鼠下丘脑染色质提取物中被优先拉下。本研究确定瘦素诱导的Stat3转录因子是Nhlh2的主要转录调节因子。由于Nhlh2转录调节黑皮质素途径中的基因，这些发现对人体体重控制具有重要意义。
