Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Cell Metab. 2011 May 4;13(5):562-72. doi: 10.1016/j.cmet.2011.02.017.
Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation.
对体重控制的分子水平理解对于对抗肥胖至关重要。我们发现，缺乏酪氨酸磷酸酶 epsilon（RPTPe）的雌性小鼠可以防止高脂肪食物、卵巢切除或衰老引起的体重增加，并表现出全身能量消耗增加和脂肪减少。缺乏 RPTPe 的小鼠，特别是雄性，表现出改善的葡萄糖稳态。非肥胖的雌性缺乏 RPTPe 的小鼠对瘦素有超敏反应，并表现出循环瘦素浓度降低，表明 RPTPe 在体内抑制下丘脑瘦素信号。在年老、卵巢切除和高脂肪喂养的缺乏 RPTPe 的小鼠中，瘦素超敏反应仍然存在，表明 RPTPe 有助于建立肥胖相关的瘦素抵抗。RPTPe 与 JAK2 结合并使其去磷酸化，从而下调瘦素受体信号。瘦素刺激诱导下丘脑 RPTPe 在其 C 端 Y695 处发生磷酸化，从而促使 RPTPe 下调 JAK2。因此，RPTPe 是体内下丘脑瘦素信号的抑制剂，并在其激活后提供对该途径的受控负反馈调节。
