Department of Physiology and Biophysics, Mississippi Center for Obesity Research, and Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi;
Department of Pharmacology and Division of Hypothalamic Research, Department of Internal Medicine, Utah Southwestern Medical Center, Dallas, Texas; and.
Am J Physiol Regul Integr Comp Physiol. 2014 Dec 15;307(12):R1438-47. doi: 10.1152/ajpregu.00131.2014. Epub 2014 Oct 22.
Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (POMC) neurons on metabolic and cardiovascular function and on chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in POMC neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5 days of stable control measurements, mice received leptin infusion (2 μg·kg(-1)·day(-1) iv) for 7 days. Compared with Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 wk of age were slightly heavier (34 ± 1 vs. 31 ± 1 g) but consumed a similar amount of food (3.9 ± 0.3 vs. 3.8 ± 0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6 ± 0.5 g) and Shp2/Pomc-cre mice (3.2 ± 0.3 g). Despite decreasing food intake, leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12 ± 1 to 6 ± 1 μU/ml and 142 ± 12 to 81 ± 8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased V̇o2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in POMC neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight.
先前的研究表明，Src 同源-2 酪氨酸磷酸酶（Shp2）是体重的重要调节因子。在这项研究中，我们研究了特异性敲除 POMC 神经元中的 Shp2 对代谢和心血管功能以及慢性血压（BP）和瘦素代谢反应的影响。Shp2 缺失的 POMC 神经元（Shp2/Pomc-cre）小鼠和对照小鼠（Shp2(flox/flox)) 被植入遥测探针和静脉导管，用于测量平均动脉压（MAP）和瘦素输注。在至少 5 天的稳定对照测量后，小鼠接受了 7 天的瘦素输注（2 μg·kg(-1)·day(-1)iv)。与 Shp2(flox/flox)对照相比，22 周龄的 Shp2/Pomc-cre 小鼠体重略重（34 ± 1 比 31 ± 1 g），但消耗的食物量相似（3.9 ± 0.3 比 3.8 ± 0.2 g/天）。瘦素输注减少了 Shp2(flox/flox) 小鼠（2.6 ± 0.5 g）和 Shp2/Pomc-cre 小鼠（3.2 ± 0.3 g）的食物摄入量。尽管减少了食物摄入量，但瘦素输注增加了对照小鼠的 MAP，而 Shp2/Pomc-cre 小鼠的 MAP 没有明显变化。瘦素输注还降低了对照组的血浆葡萄糖和胰岛素水平（12 ± 1 至 6 ± 1 μU/ml 和 142 ± 12 至 81 ± 8 mg/100 ml），但 Shp2/Pomc-cre 小鼠没有。瘦素使对照组的 V̇o2 增加了 16 ± 2%，Shp2/Pomc-cre 小鼠增加了 7 ± 1%。这些结果表明，POMC 神经元中的 Shp2 信号传导有助于瘦素的长期血压和抗糖尿病作用，并可能在正常体重调节中发挥适度作用。
