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

肥胖、糖尿病和相关疾病如高血压是患者的严重健康负担，也是医疗保健服务的压力。一类越来越多地在临床上用于治疗肥胖症（和糖尿病）的药物是胰高血糖素样肽-1（GLP-1）受体激动剂（GLP-1 RA）。GLP-1是一种由我们的肠道产生的激素，在饭后释放到血液中。它的主要作用是帮助保持低血糖，但它也会产生饱腹感，即饱足感。GLP-1 RA复制激素GLP-1的作用，这就是它们如何抑制进食。有趣的是，GLP-1也在大脑中产生，并在那里发挥作用以抑制进食。人们普遍认为，GLP-1 RA也模拟大脑释放的GLP-1的作用，这有助于其抗肥胖作用。然而，我们的实验室现在已经表明，情况并非如此，而是大脑中产生GLP-1的神经细胞（PPG神经元）的激活独立于临床使用的GLP-1 RA并抑制进食。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扮演着各种角色;它们减少食物摄入量，但它们也会提高心率，减少饮酒量，改变体温并在我们对压力的反应中发挥作用。我们假设这些细胞的不同亚群支配着这些不同的功能。因此，这项研究的主要目的是确定那些实现不同功能的PPG神经元的不同亚群，然后选择性地激活那些抑制食物摄入的神经元用于肥胖治疗，甚至可能抑制另一组提高心率的神经元。详细了解这些PPG神经元群如何实现其功能并揭示其个体特性，将有助于设计一种可用于患者的新型治疗策略。

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.