Expression Patterns of Key Receptors Revealed in the Hypothalamus
There is mounting evidence that gut-derived peptide hormones significantly affect the entire body. By binding themselves to the respective receptors in the brain, the hormones can, among other things, modulate food intake and metabolic parameters. However, to date, the role played by these peptide receptors during critical developmental phases has been the subject of very little research. Researchers from the Junior Research Group of Neurocircuit Development and Function at DIfE took a closer look and investigated the expression patterns of key receptors in the hypothalamus of mice. Their newly acquired knowledge was published in the journal ‘PLOS One’.
The hypothalamus is a crucial area of the brain responsible for controlling metabolism. It is already known that this brain region is influenced during development by changes to the mother’s diet, especially when foods are consumed which are high in fat and sugar. Until now, the underlying mechanisms for this have been subject to very little research.
Three receptors performing crucial functions
Against this backdrop, the team led by Dr. Rachel Lippert, Head of the Junior Research Group of Neurocircuit Development and Function, used a mouse model to investigate the three central receptors for gut-derived peptide hormones and their regulation in the hypothalamus during the first three weeks of life. In mice, this developmental phase roughly corresponds to the last trimester of pregnancy regarding human brain development. The receptors investigated are the gastric inhibitory polypeptide receptor (GIPR), the glucagon-like peptide 1 receptor (GLP1R), and the cholecystokinin 2 receptor (CCK2R). All three receptors are essential in glucose homeostasis, food intake, and energy balance. Furthermore, they gained popularity as a potential therapeutic target for treating obesity and diabetes.
Transferring Mice Brain Slices to a Slide using a Brush. © David Ausserhofer/DIfE
Determining the basic state
The basic state must be determined before investigating how gut-derived peptide hormones and their respective receptors in the hypothalamus are modified under certain dietary conditions. To enable this, the mother mice in this experiment received a standardized diet, and their progeny nursed with the mother’s milk. At pre-defined times during their first three weeks of life, the researchers collected tissue samples from the hypothalamus of the mice to determine the expression patterns of the three receptors. “Only after understanding how these receptors change during development can we focus on their role in neuronal network development,” stresses Lippert. These findings were the basis for the first published research of Lippert's junior research group, founded in 2020.
Specific expression patterns identified
Contrary to the researchers’ expectations, GIPR expression showed a significant fall during development. In contrast, during early postnatal development, GLP1R expression increased continuously. For CCK2R expression, the researchers observed a gender-specific pattern during the postnatal period. While CCK2R expression in male mice increased significantly during development, it remained almost constant in female mice. This points to differing roles of these receptors according to gender. “Our findings suggest that the developing brain reacts to peripheral metabolic signals. This is shown by the dynamic regulation observed in the investigated receptors during the early-stage brain development,” says lead author Dr. Lídia Cantacorps.
The Junior Research Group of Neurocircuit Development and Function Headed by Dr. Rachel Lippert (Front Center). © Susann Ruprecht/DIfE
The researchers also conducted another step in which they investigated the potential correlations between receptor expression and physiological parameters, such as body weight and blood glucose levels. While the blood glucose level showed no significant correlations, a clear correlation was identified between receptor expression and body weight. GLP1R and CCK2R positively correlated with body weight, with GIPR expression demonstrating a significant negative correlation.
The influence of diet as a future research focus
The extensive analysis showed the complexity of the interplay between gut-derived peptide hormones and their receptors during brain development. The discovery of the development-related dynamic of these receptors clears the way for a deeper understanding of how circulating gut hormones stemming from the mother influence the brain development of the progeny. “Our findings will contribute to our future research into the influence of unhealthy maternal dietary habits on gut-derived peptide hormone circulation and the brain development of their offspring,” explains Lippert. Furthermore, the findings contain enormous potential to help refine therapeutic strategies and interventions used to treat metabolic disorders, while providing insights into the complex relationship between metabolism and brain development.
This work was funded by the German Research Foundation (DFG) as part of the NeuroCure Cluster of Excellence and the German Center for Diabetes Research (DZD).
Cantacorps, L., Coull, B. M., Falck, J., Ritter, K., Lippert, R. N.: Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus. PLoS One 18(8):e0290043 (2023). [Open Access]
Background information on the three receptors
The gastric inhibitory polypeptide receptor (GIPR) is expressed in the pancreas, stomach, heart, kidneys, liver, adipose tissue, and brain. It acts as a signal transducer within the gut-brain axis. While activating the receptor in the pancreas stimulates insulin release, the effects of GIPR in the brain result in reduced food intake and weight loss.
The glucagon-like peptide 1 receptor (GLP1R) is present in the pancreas, lungs, stomach, heart, kidneys, and brain. It is involved in the control of blood glucose levels via stimulation of insulin release in the pancreas. The activation of the receptor in the hypothalamus leads to reduced food intake.
The cholecystokinin 2 receptor (CCK2R) is expressed in the brain, especially in the hypothalamus. It functions as a signal transducer within the gut-brain axis and is involved in digestion, emotional, and memory regulation processes.
Background information on the Junior Research Group of Neurocircuit Development and Function
Since February 2020, the Junior Research Group of Neurocircuit Development, headed by Dr. Rachel Lippert, has been a positive addition to Research Focus III (food choice and nutritional behavior) at DIfE. The team aims to uncover how neurocircuits, involved in controlling energy homeostasis, develop within complex networks in the brain and how they function.
Dr. Rachel Lippert
Head of the Junior Research Group Neural Circuits
Phone.: +49 33 200 88 - 2470
Phone: +49 33200 88-2335
The German Institute of Human Nutrition (DIfE) is a member of the Leibniz Association. It investigates the causes of diet-related diseases in order to develop new strategies for prevention and therapy and to provide dietary recommendations. Its research focus includes the causes and consequences of the metabolic syndrome, which is a combination of obesity, high blood pressure, insulin resistance and lipid metabolism disorder, as well as the role of diet in healthy aging and the biological basis of food choices and eating habits. In addition, DIfE is a partner of the German Center for Diabetes Research (DZD), which was founded in 2009 and has since been funded by the BMBF. The DIfE is a member of the Leibniz Association. It investigates the causes of diet-related diseases in order to develop new strategies for prevention and therapy and to provide dietary recommendations. Its research focus includes the causes and consequences of the metabolic syndrome, which is a combination of obesity, high blood pressure, insulin resistance and lipid metabolism disorder, as well as the role of diet in healthy aging and the biological basis of food choices and eating habits. In addition, DIfE is a partner of the German Center for Diabetes Research (DZD), which was founded in 2009 and has since been funded by the BMBF. www.dife.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