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

肠道激素 LEAP2（一种内源性生长素释放肽拮抗剂，也是肥胖、糖尿病、恶病质和成瘾的靶标）的人体实验医学研究

• 批准号: MR/T017279/1
• 负责人: Anthony Goldstone
• 金额: $ 122.91万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT017279%2F1
• 关键词: Human; experimental; medicine; studies; gut

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.

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。人们减肥后，随着时间的推移，体重反弹是很常见的，这在一定程度上是由肠道和体内脂肪细胞产生的激素的变化所驱动的，这些激素会作用于大脑，影响行为和食欲。其中一种是胃促生长素，这是一种由胃产生的激素，当人们禁食或减肥时，血液中的生长素会增加，而当他们吃东西或体重增加时，血液中的生长素会下降。胃饥饿素通过作用于饥饿和奖励回路，刺激食欲、食物摄入和大脑对看到食物的反应，也被认为会导致压力引起的暴饮暴食。胃饥饿素也刺激消费和寻求酒精的动机。大脑中类似的回路调节着我们对食物、酒精和其他滥用药物的行为。因此，阻断胃饥饿素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，特别是保持减肥效果，同时减少酒精摄入量，防止酒精依赖者复发。最近发现了一种叫做LEAP2的新激素，它是在肠道中产生的，在动物研究中，LEAP2阻断了胃饥饿素在其受体上的作用。当人们减肥或增重、禁食或进食时，血液中LEAP2的水平与胃饥饿素的方向相反。然而，目前关于LEAP2是否对人类有同样的作用，或者它是否有治疗肥胖和成瘾的潜力，我们知之甚少。为了了解LEAP2在人体中的作用，本研究将进行以下工作：(i)首次向健康参与者提供LEAP2激素，以评估安全性以及需要给予多少才能将血液水平提高到略高于正常水平；（ii）观察对不肥胖的健康人仅在几小时内静脉注射这种激素是否会降低他们的食欲和食量，以及它是否也会改变血液中的血糖水平和其他激素水平（激素输注将与安慰剂输注进行比较）；（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，或玩一个可以赢得金钱、食物或酒精奖励的游戏，或看到不愉快的图像（作为压力源）时，是否给予这种激素会减少大脑的激活；（iv）观察是什么改变了血液中的LEAP2水平，通过测量那些已经从以前的研究中储存了血液样本的人的血液水平，在他们减肥之前和之后，无论是通过节食，接受肥胖手术或其他帮助减肥的程序，还是在他们吃饭或服用其他影响食欲的肠道激素时。这一信息将使我们能够看到，针对LEAP2是否将是一种有价值的方法，可以开发治疗肥胖、糖尿病和酒精成瘾的新药，也可以在相反的情况下，用于治疗导致食欲不振和体重下降的疾病。

项目成果

Correlations of post-prandial changes in plasma appetitive gut hormones LEAP2 and acyl ghrelin with post-prandial decreases in appetite, and food cue reactivity, appeal and intake in adults without obesity

餐后血浆食欲性肠道激素 LEAP2 和酰基生长素释放肽的变化与餐后食欲下降以及非肥胖成人食物提示反应性、吸引力和摄入量的相关性

• 发表时间: 2022
• 作者: Luur S

Correlations between plasma ghrelin and human appetite and food intake: a systematic review and meta-analysis

血浆生长素释放肽与人类食欲和食物摄入之间的相关性：系统评价和荟萃分析

• 发表时间: 2022
• 作者: Rodriguez Flores M

Fasting plasma acyl ghrelin to LEAP2 ratio is positively correlated with human appetite and food intake, and negatively correlated with high-energy food cue reactivity in posterior cingulate cortex

空腹血浆酰基胃饥饿素与LEAP2的比率与人类食欲和食物摄入量呈正相关，与后扣带皮层的高能食物提示反应性呈负相关

• 发表时间: 2022
• 作者: Goldstone AP

Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review.

• DOI: 10.1111/acer.14967
• 发表时间: 2022-12
• 期刊: Alcoholism, clinical and experimental research

Investigating metabolic and hormonal influences on post-prandial increase of plasma satiety liver/intestinal hormone LEAP2 in adults without obesity

研究代谢和激素对非肥胖成人餐后血浆饱腹感肝/肠激素 LEAP2 增加的影响

• 发表时间: 2022
• 作者: Bhargava R