Plum Leona, Ma Xiaosong, Hampel Brigitte, Balthasar Nina, Coppari Roberto, Münzberg Heike, Shanabrough Marya, Burdakov Denis, Rother Eva, Janoschek Ruth, Alber Jens, Belgardt Bengt F, Koch Linda, Seibler Jost, Schwenk Frieder, Fekete Csaba, Suzuki Akira, Mak Tak W, Krone Wilhelm, Horvath Tamas L, Ashcroft Frances M, Brüning Jens C
Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne (CMMC), Cologne, Germany.
J Clin Invest. 2006 Jul;116(7):1886-901. doi: 10.1172/JCI27123. Epub 2006 Jun 22.
Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.
瘦素和胰岛素已被确定为燃料传感器，部分通过其下丘脑受体发挥作用，以抑制食物摄入并刺激能量消耗。由于它们的细胞内信号在PI3K途径上汇聚，我们通过特异性地使这种细胞类型中的磷脂酰肌醇3,4,5 - 三磷酸介导（PIP3介导）信号的PIP3磷酸酶Pten基因失活，直接研究了PIP3介导的信号在下丘脑促黑素皮质素（POMC）神经元中的作用。在此我们表明，Pten的POMC特异性破坏导致食欲亢进和性别二态性饮食敏感性肥胖。尽管瘦素能有效刺激POMC细胞特异性Pten基因敲除（PPKO）小鼠的POMC神经元中Stat3磷酸化，但它在体内未能显著抑制食物摄入。由于ATP敏感性钾（KATP）通道活性增加，PPKO小鼠的POMC神经元表现出明显的超极化和基础放电率降低。瘦素无法在PPKO POMC神经元中引发电活动，但应用PI3K抑制剂LY294002和KATP阻滞剂甲苯磺丁脲可恢复这些小鼠POMC神经元的电活动和瘦素诱发的放电。此外，脑室内注射甲苯磺丁脲消除了PPKO小鼠的食欲亢进。这些数据表明，PIP3介导的信号通过调节KATP通道是黑皮质素系统的关键调节因子。
