Obesity affects over 700 million people worldwide and is responsible for approximately 7% of all deaths. Europe has the second-highest proportion of overweight or obese individuals, following the U.S. Lifestyle changes alone have proven insufficient in addressing the obesity pandemic, and bariatric surgery is typically reserved for only the most extreme cases. Although pharmacotherapy is the only scalable treatment option to meet the medical demand, safe and effective therapies were until the very recent approval of the GIPR:GLP-1R co-agonist tirzepatide (Mounjaro®) not available. Strikingly, in phase 3 trials, tirzepatide lowered HbA1c up to -2.6%, while decreasing body weight in majority of patients, and with favorable tolerability, by >20%. While GLP-1R agonism is well-known to decrease body weight via centrally-regulated inhibition of food intake, it is currently unclear if and how GIP affects energy metabolism. Building up on our demonstration that GIP acts centrally in the CNS to decrease body weight via inhibition of food intake (Zhang et al., Cell Metabolism 2021), we set-off in TRUSTED to delineate how and where GIPR signal modification in the brain and the periphery affects energy, glucose and lipid metabolism. Specific objectives include generation of the first connectivity map of the GIPR network in the unsectioned brain (AIM 1), to identify the central target regions of GIPR (ant)agonists and of GLP-1R/GIPR co-agonists (AIM 2), to delineate their cellular and molecular signal mechanisms (AIM 3) and to assess functional relevance of GIPR signal modification in key neuronal/cellular populations and the periphery (AIM 4). Overall, the studies performed in TRUSTED aim to advance the knowledge of how GIPR (ant)agonists and GLP-1R/GIPR co-agonists act in the brain and the periphery to regulate energy and glucose metabolism in order to illuminate the paths for the development of next generation drugs to treat obesity and type 2 diabetes.
