Human experimental medicine studies of gut hormone LEAP2, an endogenous ghrelin antagonist and target for obesity, diabetes, cachexia and addiction

肥胖和酒精依赖是主要的健康负担，具有重大的经济、社会和社会影响。在人们减肥后，随着时间的推移，他们通常会恢复体重，这在一定程度上是由肠道和体内脂肪细胞产生的荷尔蒙的变化推动的，这些荷尔蒙作用于大脑，影响行为和食欲。其中之一是胃促生长素，这是一种由胃产生的激素，当人们禁食或减肥时，血液中的生长激素会增加，当他们吃东西或体重增加时，它会下降。Ghrelin通过作用于饥饿和奖赏回路来刺激食欲、食物摄入量和大脑对食物的反应，也被认为是压力导致的暴饮暴食。Ghrelin还刺激消费和寻求酒精的动力。大脑中类似的回路使我们对食物、酒精和其他滥用药物的行为重新产生反应。因此，阻断Ghrelin在体内的作用可能是一种潜在的治疗方法，可以帮助人们最初减肥，特别是保持减肥，并减少酒精消耗量，防止酒精依赖者复发。最近，一种名为Leap2的新激素被发现，它是在肠道中产生的，在动物研究中，Leap2阻止了Ghrelin在其受体上的作用。当人们体重减轻或增加，或禁食或进食时，血液中Leap2的水平与Ghrelin的水平相反。然而，关于Leap2是否对人类具有同样的效果，或者它是否有可能用于治疗肥胖和成瘾，目前还知之甚少。为了了解Leap2在人类中的作用，这项研究将执行以下操作：(I)首次给健康参与者注射Leap2激素，以评估安全性，以及需要给多少激素才能将血液水平提高到略高于正常水平：(Ii)观察仅在几个小时内给不肥胖的健康人注射这种激素是否会降低他们的食欲和进食量，是否也会改变血液中的血糖水平和其他激素的水平(激素注射将与安慰剂水注射进行比较)；(Iii)使用大脑核磁共振扫描，看看当他们看到食物或酒精的图片时，给予这种荷尔蒙是否会降低大脑的激活，或者玩一个游戏，在游戏中，他们可以赢得金钱、食物或酒精奖励的分数，或者看到令人不快的图像(作为压力源)；以及(Iv)通过测量那些已经存储了以前研究的血液样本的人在减肥前后的水平，无论是节食、肥胖手术或其他帮助减肥的程序，以及他们吃饭时或服用其他可能影响食欲的肠道激素时，血液中Leap2水平的变化。这些信息将使我们能够看到，针对Leap2是否是一种值得开发治疗肥胖症、糖尿病和酒精成瘾的新药的方法，在相反的情况下，也适用于患有导致食欲不振和体重下降的疾病的人。

Obesity, and alcohol dependence are major health burdens, with significant economic, social and societal impacts. After people lose weight it is common for them to regain this weight over time, and this is driven in part by changes in hormones producd by the gut and fat cells in the body which act on the brain to influence behaviour and appetite. One of these is ghrelin, a hormone produced by the stomach, that increases in the blood when people fast or lose weight, and falls when they eat food or gain weight. Ghrelin stimulates appetite, food intake and the brain's responses to seeing food by acting on the hunger and reward circuits, and is also thought to cause stress-induced overeating. Ghrelin also stimulates consumption and motivation to seek alcohol. Similar circuits in the brain reglate our behaviours to food as well as alcohol and other drugs of abuse. Blocking the action of ghrelin in the body may therefore be a potential treatment to help people lose weight initially or particularly to maintain their weight loss, as well as reducing alcohol consumption and preventing relapse in those with alcohol dependence.Recently a new hormone has been discovered called LEAP2, that is produced in the gut, and in animal studies LEAP2 blocks the action of ghrelin at its receptor. Levels of LEAP2 in the blood move in the opposite direction to ghrelin as people lose or gain weight, or fast or eat food. However, little is currently known about whether LEAP2 has the same effects in humans, or if it may have a potential as a treatment for obesity and addiction. To understand what LEAP2 does in humans this study will perform the following: (i) for the first time give LEAP2 hormone to healthy participants to assess safety and how much one needs to give to increase blood levels to a slightly higher than normal level: (ii) see if giving this hormone over several hours only, as an infusion into a vein, to healthy people who are not obese, reduces their appetite and how much they eat, and whether it also changes sugar levels in the blood and the levels of other hormones (the hormone infusion will be compared with placebo water infusion);(iii) use brain MRI scanning to see if giving this hormone reduces brain activation when they see pictures of food or alcohol, or play a game where they can win points towards money, food or alcohol rewards, or see unpleasant images (as a stressor); and (iv) see what things change LEAP2 levels in the blood by measuring the levels in people who have already had blood samples stored from previous studies, before and after they have lost weight, either from dieting, having obesity surgery or other procedures to aid weight loss, and also when they eat a meal, or are given other gut hormones that can affect appetite.This information will enable us to see if targeting LEAP2 will be a worthwhile approach to develop new medicines for the treatment of obesity, diabetes, and addiction to alcohol, and also in the reverse situation, for people with illnesses that cause them to lose appetite and their weight.