Liraglutide's impact on reward brain circuits in human obesity to be investigated in a 70-patient RCT

Obesity is a complex chronic disease driven by multiple factors, including dysregulation of brain reward pathways that influence food intake and cravings. Current standard-of-care treatments often fall short in achieving sustained weight loss, highlighting the need for interventions that target underlying neurobiological mechanisms. GLP-1 receptor agonists like liraglutide are approved for obesity management, primarily by enhancing satiety and reducing appetite via central and peripheral mechanisms. However, their specific effects on the brain's reward circuitry, particularly in patients without diabetes, remain an area requiring deeper investigation to optimize therapeutic strategies.

This randomized controlled trial (RCT) will enroll 70 obese patients without diabetes, evaluating them at baseline and after 16 weeks of daily subcutaneous injections of liraglutide 3.0 mg (Saxenda®) or placebo via pen injector. Participants will undergo a functional Magnetic Resonance Imaging (fMRI) session while presented with gustatory stimuli to assess brain reward circuit activity. Behavioral tasks, including 'liking versus wanting' assessments performed in the scanner, will differentiate hedonic and motivational aspects of food intake. Questionnaires will evaluate subjective reward mechanisms and emotional regulation abilities. Metabolic parameters and appetite-regulating hormones will also be assessed and correlated with fMRI and behavioral findings. A control group of normal body weight individuals will be evaluated once at baseline.

The primary objective is to elucidate how liraglutide 3.0 mg influences central reward pathways and contributes to weight loss in obesity. Researchers will quantify changes in brain activity using fMRI while participants are presented with gustatory stimuli, comparing responses at baseline and after 16 weeks of treatment. Specifically, the study aims to identify alterations in neural circuits associated with food reward processing, such as those involving the nucleus accumbens and ventromedial prefrontal cortex. Furthermore, behavioral tasks, including 'liking versus wanting' assessments performed within the scanner, will be used to differentiate hedonic and motivational aspects of food intake. The central hypothesis is that liraglutide will modulate these reward circuits, leading to reduced food cravings and improved control over intake, thereby facilitating weight loss. Questionnaires will evaluate subjective reward mechanisms and emotional skills, such as emotional regulation ability, which are known to influence eating behaviors. Additionally, a comprehensive panel of metabolic parameters and hormones involved in appetite regulation will be assessed and correlated with both fMRI findings and behavioral outcomes. These include, but are not limited to, fasting glucose, insulin, HbA1c, leptin, ghrelin, and GLP-1 levels, providing a holistic view of the drug's impact on both central and peripheral mechanisms. The study expects to observe significant changes in these markers, reflecting the drug's therapeutic effects on obesity.