Periodic Reporting for period 1 - TRUSTED (CenTral and PeRipheral NervoUs SyStem acTion of GIPR in ObEsity and Diabetes)
Reporting period: 2022-09-01 to 2025-02-28
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.
While data related to AIM 1 are still being analyzed, we demonstrated in AIM 2 that long-acting GIPR agonists primarily reach specific areas in the circumventricular organs of the brain, namely the median eminence of the hypothalamus and the area postrema of the hindbrain, from where they project feeding related information to key feeding neurocircuitries in deeper brain areas (Liskiewicz et al., Nature Metabolism 2023) to control energy metabolism.
Research highlights made in TRUSTED include several key discoveries regarding the role of long-acting GIPR agonists in metabolism and weight regulation. We showed that GIPR agonists target specific brain regions in the hypothalamus and hindbrain to regulate energy metabolism and body weight by influencing feeding-related neurocircuits in deeper brain areas. Additionally, we demonstrated that GIPR agonists control body weight and food intake via inhibitory GABAergic neurons of the hindbrain (Liskiewicz et al., Nature Metabolism 2023). Furthermore, we showed that that GIPR agonism improves LDL cholesterol levels and reduces atherosclerosis, even at doses too low to affect body weight and food intake, indicating its broader therapeutic potential beyond just treatment of obesity and diabetes (Sachs et al., Cardiovascular Diabetology 2023). We also demonstrated that the GIPR:GLP-1R co-agonist tirzepatide engages different mechanisms in mice and humans for insulin secretion, urging caution when translating rodent-based findings to humans (El et al., Nature Metabolism 2023) and found GIPR agonism and antagonism to affect body weight and food intake via different and non-overlapping signal mechanisms (Gutgesell & Khalil, under review).