The increasing amount of patients with obesity and type 2 diabetes benefit greatly from the recently developed GIPR:GLP-1R co-agonists. These novel compounds lead to substantial weight loss, offering a revolutionary approach to patients worldwide. Although the hormone glucose-dependent insulinotropic polypeptide (GIP) was already shown by Helmholtz Munich scientists to decrease body weight via the brain GIP receptor, the underlying neurons through which GIP acts in the brain remained unknown. Scientists led by Dr. Timo Müller from Helmholtz Munich and the German Center for Diabetes Research (DZD) have now discovered that GIP decreases body weight by interacting with specific inhibitory neurons in the brain. These new findings are published in 'Nature Metabolism'.

Obesity and type 2 diabetes are two closely interconnected health challenges that are on the rise globally. Recent breakthroughs in the treatment were pioneered by Helmholtz Munich scientists and led to the development of so-called GIPR:GLP-1R co-agonists. These are compounds designed to target two specific hormone receptors in the human body: glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R). The receptors are involved in regulating glucose metabolism and insulin secretion and their pharmacological targeting promotes weight loss and reduction in food intake. However, the exact mechanisms and specific neuronal populations through which the hormone glucose-dependent insulinotropic polypeptide (GIP) affects energy balance and food intake remained so far largely elusive. 

GIP Induces Weight Loss through Inhibitory Neurons in the Brain
Dr. Timo Müller and his team shed light on the underlying molecular mechanisms and the role of GIP. In their new study, the researchers demonstrate that GIP acts in the brainstem via specific inhibitory neurons. In detail, the GIPR:GLP-1R co-agonist reduces body weight and food intake through GIPR signaling in inhibitory neurons in the brain, the so-called GABAergic neurons. If the GIPR is absent in these GABAergic neurons, the weight-reducing effects of GIP vanish.

The picture shows in red the accumulation of GIP in the brain stem after a single peripheral injection and in green the resulting activation of neurons. Copyright:  Nature Metabolism | ©Liskiewicz et al.

“For the first time, these data illustrate that GIP regulates body weight and food intake in the brain by stimulating GABAergic neurons and emphasizes the necessity of the GIPR on these neurons for this ability to decrease body weight and food intake”, says Timo Müller, senior author of the paper. “Our data offer valuable insights into the mechanisms of GIPR:GLP-1R co-agonists, which can now be used to specifically target the brain GIP system for next generation anti-obesity drugs”, adds Arek Liskiewicz, first author of the study.

Original publication:
Liskiewicz et al. (2023): Glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via GABAergic neurons in mice. Nature Metabolism. DOI: 10.1038/s42255-023-00931-7
 

Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies and chronic lung diseases. With the power of artificial intelligence and bioengineering, the researchers accelerate the translation to patients. Helmholtz Munich has more than 2,500 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 43,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en

The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Munich – German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of Helmholtz Munich at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Munich at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. www.dzd-ev.de/en