Analysis of the brain GLP-1 circuitry at cellular level to characterise its roles in the control of food intake

肥胖、糖尿病和高血压等相关疾病是患者的严重健康负担，也是医疗服务的压力。临床上越来越多地用于治疗肥胖(和糖尿病)的一类药物是胰高血糖素样肽-1(GLP-1)受体激动剂(GLP-1RAs)。GLP-1是一种由我们的肠道产生的激素，在用餐后释放到血液中。它的主要作用是帮助保持血液中的低糖，但它也会产生饱腹感，即饱足感。GLP-1RAs复制了荷尔蒙GLP-1的作用，这就是它们抑制进食的方式。有趣的是，GLP-1也在大脑中产生，并在那里起到抑制进食的作用。人们普遍认为，GLP-1RAs也模仿大脑释放的GLP-1的作用，这有助于它们的抗肥胖作用。然而，我们的实验室现在证明情况并非如此，而是大脑中产生GLP-1的神经细胞的激活，即PPG神经元，独立于临床使用的GLP-1RAs而抑制进食。虽然这是一个非常令人兴奋的发现，但PPG神经元在我们的大脑中发挥着各种作用；它们减少了食物的摄入量，但它们也提高了心率，减少了酒精消耗，改变了体温，并在我们对压力的反应中发挥了作用。我们假设这些细胞的不同亚群管理着这些不同的功能。因此，这项研究的主要目的是识别那些满足不同功能的PPG神经元的不同亚群，然后选择性地仅激活那些抑制肥胖治疗的食物摄入的神经元，甚至可能抑制另一组这样的神经元，从而提高心率。详细了解这些PPG神经元组是如何履行其功能并揭示其个体特性的，将有助于设计一种对患者有效的新治疗策略。

Obesity, diabetes, and associated diseases such as hypertension, are a serious health burden for patients and a strain on healthcare services. A class of drugs that are increasingly being used clinically to treat obesity (and diabetes) are glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs). GLP-1 is a hormone that is produced by our gut and released into the blood after a meal. Its main role is to help keeping sugars low in the blood, but it also generates the feeling of fullness, i.e. satiation. GLP-1RAs reproduce the effect of the hormone GLP-1 and that is how they suppress eating.Interestingly, GLP-1 is also produced in the brain, and acts there to suppress eating. It has been widely assumed that GLP-1RAs also mimic the action of GLP-1 released by the brain and that this contributes to their anti-obesity effect. However, our laboratory has now shown that this is not the case, but that activation of the nerve cells in the brain that produce GLP-1, the PPG neurons, suppress eating independently from and in addition to clinically-used GLP-1RAs. Whilst this is a highly exciting finding PPG neurons fulfil a variety of roles in our brain; they reduce food intake, but they also raise heart rate, reduce alcohol consumption, change body temperature and play a role in our response to stress. We hypothesise that different subgroups of these cells govern these different functions. Thus, the major aim of this research is to identify those different subgroups of PPG neurons that fulfil the different functions, and then selectively activate only those that suppress food intake for obesity treatment, and possibly even inhibit another group of these neurons that raises heart rate. Understanding in detail how these PPG neuron groups fulfil their functions and revealing their individual properties will then facilitate the design a novel treatment strategy that could work in patients.