1] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Department of Molecular and Integrative Physiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Nat Med. 2014 May;20(5):484-92. doi: 10.1038/nm.3527. Epub 2014 Apr 20.
Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre(+) Pten(flox/flox) mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip(+) neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.
炎症在胰岛素抵抗的发展中起着关键作用。最近的证据表明，中枢神经系统通过抗炎反射在调节外周炎症方面起着重要作用。然而，这一现象在 2 型糖尿病发病机制中的重要性仍不清楚。在这里，我们发现大鼠胰岛素-2 启动子（Rip）介导的 Pten 缺失，即编码 PI3K 信号负调节剂的基因，导致外周组织中 M2 激活的巨噬细胞介导的胆碱能抗炎途径的激活。因此，与同窝对照相比，Rip-cre(+) Pten(flox/flox) 小鼠在基础条件下表现出较低的全身炎症和更高的胰岛素敏感性，而当用乙酰胆碱受体拮抗剂治疗或耗尽巨噬细胞时，这种情况就会消失。高脂饮食喂养后，Pten 缺失的小鼠仍然保持明显的胰岛素敏感性，这与大量皮下脂肪扩张有关。它们还表现出更多的脂肪生成和 M2 巨噬细胞浸润，这两者都在通过左侧迷走神经切断破坏抗炎传出途径后被消除。总之，我们表明，Rip(+)神经元中的 Pten 表达通过介导抗炎反射在糖尿病发病机制中起着关键作用。
