Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age
Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age
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DOI：
10.1210/en.2006-0672
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发表时间：
2007-01-01
期刊：
影响因子：
4.8
通讯作者：
Gettys, Thomas W.
中科院分区：
文献类型：
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作者：
Morrison, Christopher D.;White, Christy L.;Gettys, Thomas W.
动物在年老时表现出中枢瘦素敏感性的降低。然而，生长，代谢和肥胖风险的变化发生在生命的早期，特别是在从青年到中年的过渡期间。为了确定中枢瘦素敏感性的初始降低何时发生，在8、12和20周龄的雄性饲料喂养的Sprague道利大鼠中测试了瘦素依赖性的食物摄取抑制。侧脑室注射瘦素（3 μ g）可抑制8周龄和12周龄大鼠24小时摄食量（P < 0.05），但对20周龄大鼠无明显影响。为了确定这种阻力的潜在细胞介质，我们专注于蛋白酪氨酸磷酸酶1B（PTP1B），最近描述的瘦素信号抑制剂。Westernblot检测20周龄大鼠下丘脑中基底膜PTP1B蛋白水平显著高于8周龄大鼠（P < 0.05）。20周龄大鼠禁食24 h后，下丘脑PTP1B水平下降（P < 0.05），与瘦素敏感性恢复一致。为了直接测试抑制PTP1B是否恢复瘦素敏感性，在瘦素之前1小时用药理学PTP1B抑制剂预处理20周龄饮食喂养的大鼠，并记录24小时的食物摄入量。正如预期的那样，单独的瘦素产生了一个小的，但不显着的减少食物摄入量。然而，用PTP1B抑制剂预处理导致瘦素依赖性摄食抑制的显著改善（P < 0.05）。这些数据是一致的假设，增加PTP1B有助于下丘脑瘦素抵抗大鼠过渡到中年。
Animals at advanced ages exhibit a reduction in central leptin sensitivity. However, changes in growth, metabolism, and obesity risk occur much earlier in life, particularly during the transition from youth to middle age. To determine when initial decreases in central leptin sensitivity occur, leptin-dependent suppression of food intake was tested in 8-, 12-, and 20-wk-old male, chow-fed Sprague Dawley rats. Intracerebroventricular leptin injection (3 mu g) suppressed 24-h food intake in 8- and 12-wk-old rats (P < 0.05) but not 20-wk-old rats. To identify potential cellular mediators of this resistance, we focused on protein tyrosine phosphatase 1B (PTP1B), a recently described inhibitor of leptin signaling. PTP1B protein levels, as determined by Western blot, were significantly higher in mediobasal hypothalamic punches collected from 20-wk-old rats, compared with 8-wk-old rats (P < 0.05). When 20-wk-old rats were fasted for 24 h, levels of hypothalamic PTP1B decreased (P < 0.05), coincident with a restoration of leptin sensitivity. To directly test whether inhibition of PTP1B restores leptin sensitivity, 20-wk-old chow-fed rats were pretreated with a pharmacological PTP1B inhibitor 1 h before leptin, and 24-h food intake was recorded. As expected, leptin alone produced a small but nonsignificant reduction in food intake. However, pretreatment with the PTP1B inhibitor resulted in a marked improvement in leptin-dependent suppression of food intake (P < 0.05). These data are consistent with the hypothesis that increases in PTP1B contribute to hypothalamic leptin resistance as rats transition into middle age.