Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Gothenburg, Sweden.
J Neurosci. 2012 Apr 4;32(14):4812-20. doi: 10.1523/JNEUROSCI.6326-11.2012.
The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.
胰高血糖素样肽 1（GLP-1）系统是 2 型糖尿病治疗的新兴靶点。除了调节葡萄糖稳态外，GLP-1 还能减少食物摄入。先前的研究表明，GLP-1 的厌食作用可以通过调节稳态进食的下丘脑和脑干回路来介导。在这里，我们在大鼠中证明了 GLP-1 诱导厌食的一种全新的神经生物学机制，涉及 GLP-1 激动剂 Exendin-4（EX4）对食物奖赏的直接作用，这些作用是在中边缘奖赏系统水平上发挥的。我们评估了外周、中枢和中边缘内 EX4 对两种食物奖赏模型的影响：条件性位置偏好（CPP）和渐进比例操作性条件作用。EX4 降低了 CPP 测试中食物奖赏的影响，因为大鼠不再喜欢以前与巧克力丸配对的环境。当 EX4 在外周给药时，它还降低了渐进比例操作性条件作用范式中蔗糖的动机行为。我们表明，这种效应是通过 GLP-1 受体（GLP-1R）介导的。GLP-1R 表达在中边缘奖赏系统的几个关键节点中；然而，它们的功能仍然未知。因此，我们试图确定食物奖赏效应的神经生物学基础。我们发现，EX4 介导的食物奖赏抑制作用可以由两个关键的中边缘结构——腹侧被盖区和伏隔核驱动，而不会同时引起不适或运动障碍。目前的研究结果表明，通过与中边缘系统相互作用，中枢 GLP-1R 的激活可以显著抑制食物奖赏/动机，这表明 GLP-1R 刺激影响摄食行为的一种全新机制。
