TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose Metabolism With Feeding
TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose Metabolism With Feeding
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DOI：
10.2337/db17-1485
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发表时间：
2018-07-01
期刊：
影响因子：
7.7
通讯作者：
Tiganis, Tony
中科院分区：
文献类型：
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作者：
Dodd, Garron T.;Lee-Young, Robert S.;Tiganis, Tony
胰岛素通过对周围组织和大脑的影响来调节葡萄糖代谢。胰岛素受体（IR）信号传导抑制下丘脑中表达AgRP的神经元，从而有助于胰岛素抑制肝葡萄糖产生（HGP），而AgRP神经元活化减弱棕色脂肪组织（BAT）葡萄糖摄取。酪氨酸磷酸酶TCPTP抑制AgRP神经元中的IR信号。下丘脑TCPTP由禁食诱导，进食后降解。在这里，我们评估的影响，TCPTP在AgRP神经元的葡萄糖代谢的控制。AgRP神经元中的TCPTP缺失（Agrp-Cre; Ptpn 2（fl/fl））增强了胰岛素敏感性，如通过增加葡萄糖输注速率所评估的，并且在高胰岛素-正常血糖钳夹期间减少了HGP，伴随着BAT和棕色白色脂肪组织中[C-14]-2-脱氧-d-葡萄糖摄取的增加。AgRP神经元中TCPTP的缺乏促进了脑室内胰岛素诱导的对其他无反应的食物限制小鼠的肝再生的抑制，但在下丘脑TCPTP水平降低的进食/饱足小鼠中没有影响。Agrp-Cre; Ptpn 2（fl/fl）小鼠中葡萄糖稳态的改善通过IR杂合性（Agrp-Cre; Ptpn 2（fl/fl）;Insr（fl/+））校正，从而将对葡萄糖代谢的影响与AgRP神经元中的IR信号传导因果联系起来。我们的研究结果表明，TCPTP控制IR信号在AgRP神经元协调HGP和棕色/米色脂肪细胞葡萄糖摄取响应喂养/禁食。
Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons (Agrp-Cre;Ptpn2(fl/fl)) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [C-14]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp-Cre;Ptpn2(fl/fl) mice was corrected by IR heterozygosity (Agrp-Cre;Ptpn2(fl/fl);Insr(fl/+)), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting.