From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (S.F., J.T., K.A.); Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (S.F., C.B., M.N., J.T., K.A.); and Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY (J.I., M.H.).
Arterioscler Thromb Vasc Biol. 2015 May;35(5):1092-100. doi: 10.1161/ATVBAHA.114.304873. Epub 2015 Feb 12.
Intestinal overproduction of atherogenic chylomicron particles postprandially is an important component of diabetic dyslipidemia in insulin-resistant states. In addition to enhancing insulin secretion, peripheral glucagon-like peptide-1 (GLP-1) receptor stimulation has the added benefit of reducing this chylomicron overproduction in patients with type 2 diabetes mellitus. Given the presence of central GLP-1 receptors and GLP-1-producing neurons, we assessed whether central GLP-1 exerts an integral layer of neuronal control during the production of these potentially atherogenic particles.
Postprandial production of triglyceride-rich lipoproteins was assessed in Syrian hamsters administered a single intracerebroventricular injection of the GLP-1 receptor agonist exendin-4. Intracerebroventricular exendin-4 reduced triglyceride-rich lipoprotein-triglyceride and -apolipoprotein B48 accumulation relative to vehicle-treated controls. This was mirrored by intracerebroventricular MK-0626, an inhibitor of endogenous GLP-1 degradation, and prevented by central exendin9-39, a GLP-1 receptor antagonist. The effects of intracerebroventricular exendin-4 were also lost during peripheral adrenergic receptor and central melanocortin-4 receptor inhibition, achieved using intravenous propranolol and phentolamine and intracerebroventricular HS014, respectively. However, central exendin9-39 did not preclude the effects of peripheral exendin-4 treatment on chylomicron output.
Central GLP-1 is a novel regulator of chylomicron production via melanocortin-4 receptors. Our findings point to the relative importance of central accessibility of GLP-1-based therapies and compel further studies examining the status of this brain-gut axis in the development of diabetic dyslipidemia and chylomicron overproduction.
餐后肠道产生动脉粥样硬化性乳糜微粒颗粒是胰岛素抵抗状态下糖尿病脂代谢紊乱的一个重要组成部分。除了增强胰岛素分泌外，外周胰高血糖素样肽-1（GLP-1）受体刺激还有额外的益处，可以减少 2 型糖尿病患者的这种乳糜微粒过度产生。鉴于中枢 GLP-1 受体和 GLP-1 产生神经元的存在，我们评估了中枢 GLP-1 是否在这些潜在的动脉粥样硬化性颗粒产生过程中发挥了神经元控制的整体作用。
给予单次侧脑室注射 GLP-1 受体激动剂 exendin-4 的叙利亚仓鼠，评估餐后富含甘油三酯脂蛋白的产生。与载体处理的对照组相比，侧脑室给予 exendin-4 可降低富含甘油三酯脂蛋白-甘油三酯和 -载脂蛋白 B48 的积累。这与中枢给予 MK-0626（内源性 GLP-1 降解抑制剂）相吻合，并被中枢给予 exendin9-39（GLP-1 受体拮抗剂）所阻止。侧脑室给予 exendin-4 的作用也在周围肾上腺素能受体和中枢黑皮质素-4 受体抑制时丢失，分别使用静脉注射普萘洛尔和酚妥拉明和侧脑室 HS014 实现。然而，中枢给予 exendin9-39 并不排除外周给予 exendin-4 对乳糜微粒输出的影响。
中枢 GLP-1 是通过黑皮质素-4 受体调节乳糜微粒产生的一种新型调节剂。我们的发现表明基于 GLP-1 的治疗方法的中枢可及性的相对重要性，并促使进一步研究检查该脑-肠轴在糖尿病脂代谢紊乱和乳糜微粒过度产生中的状态。
