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

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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.