PDF(Pubmed)
Abstract：
Glucagon-like peptide-1 (GLP-1) analogs represent a new class of weight-loss medication, which has recently exponentially grown in popularity. GLP-1 is produced in the intestinal L cells in response to macronutrient intake, but it is also produced in the brain in a subset of neurons in the nucleus of the solitary tract (NTS). Exogenously-delivered GLP-1 analogs reduce food intake and food-motivated behavior in male and female rats, with some sex divergence of these effects in specific brain sites. These analogs potentially target GLP-1 receptors endogenously supplied by the gut and brain-produced GLP-1. The function of the NTS GLP-1-producing neurons [Gcg neurons] is still relatively unknown in rats. Moreover, even less is understood about the function of these neurons in females. We have recently developed a transgenic rat that expresses Cre under the Gcg promoter. Here, we interrogate this new animal model with optogenetics and chemogenetics to determine whether activation of the NTS GLP-1 neurons affects ingestive and motivated behavior in male and female rats. Optogenetic activation of the NTS Gcg neurons robustly reduced chow intake in both male and female rats. Interestingly, motivated behavior for a sucrose reward was reduced exclusively in females. To ensure that this unexpected sex difference was not activation method-specific, we next virally introduced excitatory DREADD receptors into the Gcg neurons and investigated the effect of chemogenetic activation of these neurons on ingestive and motivated behavior. Even upon chemogenetic activation, female rats reduced their motivation to obtain the sucrose reward, yet no effect on this behavior was observed in males. Our results show that activation of hindbrain Gcg neurons is sufficient to reduce food intake in both sexes. In females, but not males, Gcg neuron activation alone is also sufficient to reduce motivated behavior for sucrose. Thus, there is a sex difference in the ability of GLP-1-producing neuron activation to control motivated behavior for food.
摘要：
胰高血糖素样肽-1（GLP-1）类似物代表了一类新的减肥药物，最近受欢迎程度呈指数级增长。GLP-1在肠道L细胞中产生，以响应大量营养素的摄入，但它也在大脑中的孤束核（NTS）的一部分神经元中产生。外源递送的GLP-1类似物减少了雄性和雌性大鼠的食物摄入和食物动机行为，这些影响在特定的大脑部位有一些性别差异。这些类似物潜在地靶向由肠和脑产生的GLP-1内源性提供的GLP-1受体。NTS产生GLP-1的神经元[Gcg神经元]的功能在大鼠中仍然相对未知。此外，对女性这些神经元的功能了解更少。我们最近开发了一种在Gcg启动子下表达Cre的转基因大鼠。这里,我们用光遗传学和化学遗传学研究了这种新的动物模型,以确定NTSGLP-1神经元的激活是否会影响雄性和雌性大鼠的摄取行为和动机行为.NTSGcg神经元的光遗传激活强烈减少了雄性和雌性大鼠的食物摄入量。有趣的是,蔗糖奖励的动机行为仅在女性中减少。为了确保这种意外的性别差异不是特定于激活方法的，接下来，我们将兴奋性DREADD受体引入Gcg神经元，并研究了这些神经元的化学遗传激活对摄取和动机行为的影响。即使在化学激活后，雌性大鼠降低了获得蔗糖奖励的动机，然而，在男性中没有观察到对这种行为的影响。我们的结果表明，后脑Gcg神经元的激活足以减少两性的食物摄入量。在女性中，但不是男性，单独的Gcg神经元激活也足以减少蔗糖的动机行为。因此，产生GLP-1的神经元激活控制食物动机行为的能力存在性别差异。
