Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.
1] Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7 [2] Departments of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Nat Commun. 2015 Jan 12;6:5970. doi: 10.1038/ncomms6970.
The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-δ→KATP-channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-δ or KATP-channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic-DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes.
大脑是肝脏富含甘油三酯的极低密度脂蛋白（VLDL-TG）的调节剂。目前尚不清楚涉及的神经回路以及脂肪酸触发神经元网络来调节 VLDL-TG 的能力。在这里，我们证明了将油酸注入中脑基底部（MBH）会激活 MBH PKC-δ→KATP 通道信号轴，以抑制大鼠的 VLDL-TG 分泌。背侧迷走神经复合体（DVC）中的 NMDA 受体介导的传递和肝神经支配都需要降低 VLDL-TG，说明了介导 MBH 脂肪酸感应的 MBH-DVC-肝迷走神经回路。高脂肪饮食（HFD）喂养会升高血浆 TG 和 VLDL-TG 分泌，并消除 MBH 油酸感应以降低 VLDL-TG。重要的是，通过肝迷走神经直接激活 MBH PKC-δ或 KATP 通道可以恢复 HFD 诱导的失调。因此，针对依赖脂肪酸感应的下丘脑-DVC 神经回路可能具有降低肝脏 VLDL-TG 和恢复肥胖和糖尿病中脂质稳态的治疗潜力。
