Pharmacotherapy of obesity: the influence of GLP-1 analogue liraglutide on brain activity and related effects on eating behavior, a literature review and meta-analysis

Introduction - Obesity is a chronic disease characterized by adipose tissue dysfunction and assessed by a body mass index (BMI) ≥ 30 kg/m2. This pathological condition is gaining relevance due to its worldwide epidemic growth over the last 30 years and its proven association with the increasing risk of developing Type 2 Diabetes Mellitus, hypertension, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). The development of the disease includes aspects of genetics, epigenetics, behaviour, and lifestyle. Obesity pathophysiology is related to an impairment of the system for energy homeostasis, to adiposopathy, insulin resistance, and gut microbiota functionality. Among the hormones involved in the gut-brain axis communication, there is Glucagon-like peptide 1, which has both insulinotropic and anorexigenic effects. This gut hormone contributes to the modulation of the central control of feeding, in the hypothalamus, and its physiology became of crucial importance in obesity pharmacotherapy. In the last 15 years, several Glp-1 receptor agonists (GLP-1RAs), such as Liraglutide, have been developed for their insulinotropic effect in patients with Diabetes Mellitus, and for their weight lowering effect in patients with obesity. The actions of GLP-1RAs in CNS have been partially investigated, and we know that they can act in the central regulation of homeostatic eating. However, about their influence on more complex psychological mechanisms, like the reward system, the scientific knowledge is still limited. Studying these aspects could help us to better understand the mechanisms behind the weight loss effect of Liraglutide, and their association with eating behaviour and appetite. Aim – Conducting a systematic review and meta-analysis on the effects of Liraglutide in people with overweight or obesity, focusing on appetite measurements, eating behaviour scores, changes in food preferences, or fMRI analysis on CNS activity in response to food. Methods – We conducted a systematic research in Pubmed and Scopus, and we screened the results to find observational or randomised controlled trials conducted on subjects with overweight/obesity that underwent Liraglutide intervention, that aimed to assess aspects of eating behaviour, appetite, food preferences, or food-related changes in brain activation (in the case of fMRI studies). In addition, for studies that showed a lower degree of heterogeneity, we conducted a meta-analysis using Overall Appetite scores (OAS) and weight loss measures, using ProMeta3 software. Results – With 20 studies, we described 4 different outcomes: eating behaviour, appetite, food preferences, and fMRI results. The main tool used in the evaluation of eating behaviour was the Three factors eating questionnaire (TFEQ), that gives scores about emotional eating, uncontrolled eating, and cognitive restraint; in most of the cases, liraglutide intervention influenced the scores. However, studies showed high heterogeneity in population and methods. Appetite was the most studied parameter, measured mainly using VAS in its components of hunger, satiety, fullness, and prospective food consumption. Liraglutide showed effects on all the scores, generally by reducing hunger and prospective food consumption and by increasing satiety and fullness. In some studies, the data were resumed in the OAS (overall appetite score), that represents appetite suppression. 5 studies were appropriate to conduct a meta-analysis using data on weight loss and OAS. The effect of liraglutide was clear for both parameters, but we were not able to infer what is the role of appetite suppression on weight loss. Data from fMRI revealed differences in activation of brain areas associated to reward mechanisms, even if results were heterogeneous. Further studies are needed to shed light on central effects of liraglutide and on the mechanisms that made it a powerful tool in the therapy for obesity.