Neuroendocrine Seeds of Obesity

Objective

Obesity prevalence is dramatically increasing worldwide. The hypothalamus seem to be a pivotal brain structure in reversing obesity, as hypothalamic activation by incretin-based therapies (IBT) reduces body weight by 25%. However, the detailed functioning of the human hypothalamus in obesity remains unknown. Therefore, my overarching objective is to characterize hypothalamic structure and function in obesity. I will collaborate with clinical obesity experts at the University of Copenhagen and a pioneering MRI research team at Brigham and Women’s Hospital. The project includes three Work Packages (WPs), each addressing a gap in current state-of-the-art knowledge: WP1: Impact of IBT on hypothalamic signaling Hypothesis: IBT partially or fully normalizes meal-induced hypothalamic signaling to reverse obesity. Sub-objective: Map how long-term IBT affects hypothalamic signaling to the rest of the brain in a large randomized controlled trial of youth with obesity. WP2: Exploring the Impact of Oxytocin on Hypothalamic Structure and Function Hypothesis: Oxytocin reduces radiological indicators of hypothalamic inflammation associated with obesity and improves hypothalamic function. Sub-objective: Characterize hypothalamic structure and function in obesity and map the effects of four weeks of intranasal oxytocin treatment. WP3: Hypothalamic Responsiveness to Incretin Hormones Hypothesis: Hypothalamic responsiveness to incretin hormones is impaired in obesity. Sub-objective: Map the responsiveness of the hypothalamus to incretin hormones in people with obesity compared to people without obesity. The output of this project will elucidate key neurobiological mechanisms underlying obesity and inform the development of sustainable strategies to treat and prevent obesity. It will also facilitate critical knowledge exchange between European and U.S. research institutions and significantly advance neuroendocrine research capacity in Europe.