Vaisse C, Halaas J L, Horvath C M, Darnell J E, Stoffel M, Friedman J M
Laboratory of Metabolic Diseases, Rockefeller University, New York, New York 10021, USA.
Nat Genet. 1996 Sep;14(1):95-7. doi: 10.1038/ng0996-95.
Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism. Leptin's precise sites of action are not known. The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus. Ob-R is a member of the gp130 family of cytokine receptors which are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, we assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor where they are phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The activation of STAT proteins in response to leptin was assayed in a variety of mouse tissues known to express Ob-R. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wild-type mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes. Our data indicate the hypothalamus is a direct target of leptin action and that this activation is critically dependent on the gp-130-like leptin receptor isoform missing in C57BLKS/J db/db mice. This is the first in vivo demonstration of leptin signal transduction.
瘦素是一种由脂肪细胞分泌的激素，通过影响饱腹感和能量代谢来调节脂肪组织的大小。瘦素的确切作用位点尚不清楚。瘦素受体（Ob-R）以多种可变剪接形式存在于许多组织中，这增加了瘦素对包括下丘脑在内的许多组织产生作用的可能性。Ob-R是细胞因子受体gp130家族的成员，已知该家族通过激活胞质STAT蛋白来刺激基因转录。为了确定瘦素在体内的作用位点，我们检测了用瘦素处理的小鼠中STAT蛋白的激活情况。STAT蛋白与配体激活受体胞质结构域中的磷酸酪氨酸残基结合，并在那里被磷酸化。激活的STAT蛋白二聚化并转移到细胞核，在那里它们结合DNA并激活转录。在已知表达Ob-R的多种小鼠组织中检测了对瘦素反应的STAT蛋白激活情况。在ob/ob和野生型小鼠的下丘脑中，注射瘦素激活了Stat3，但未激活其他STAT蛋白，而在缺乏瘦素受体异构体的突变体db/db小鼠中则未激活。瘦素在任何其他测试组织中均未诱导STAT激活。瘦素对Stat3的激活呈剂量依赖性，在15分钟后首次观察到，30分钟时达到最大值。我们的数据表明下丘脑是瘦素作用的直接靶点，并且这种激活严重依赖于C57BLKS/J db/db小鼠中缺失的gp-130样瘦素受体异构体。这是瘦素信号转导的首次体内证明。
