Insulin Action and Resistance in the Brain
Hubert Preißl | Jens Brüning | Cristina García Cáceres
Current studies show that the brain plays an important role in the development of type 2 diabetes and obesity. For example, brain areas react to the hormone insulin, which are important for food intake or metabolism. It is assumed that the hormone in the brain reduces the feeling of hunger.
In this academy, DZD researchers investigate the connection between the brain and metabolism. They focus on translational and multicenter studies. In this way, the strengths of the DZD partners can be combined in the basic and translational neurosciences. The research covers the entire life span – from fetus to elderly person.
Besides investigations in mechanistic animal models – in rodents, but also in large animal models, e.g. pigs – human data with excellent phenotypic characterization are collected in studies. Members of the Academy have access to advanced brain imaging tools, including high-field MRI, combined positron emission tomography/magnetic resonance imaging (PET-MRI), optogenetics (a biological technology to control cellular activity with light) and electrophysiology (a branch of neurophysiology dealing with electrochemical signal transmission in the nervous system).
The researchers are focusing on the following topics:
- Characterization and treatment of phenotypes associated with insulin resistance in the brain
- Identification of the interaction of the maternal metabolism with the autonomic nervous system of the human fetus and brain development
- Deciphering the role of neurons and glial cells in controlling energy metabolism in the brain for health and diet-related obesity
- Analysis of neural circuits for CNS-dependent control of metabolism and translation of the results in human studies
- Evaluation of the effects of oxytocin on metabolic control
Multicenter studies and research results
Insulin resistance of certain areas of the brain has a negative effect on the metabolism. The interaction between insulin and dopamine appears to play a crucial role. In the clinical DAG study (dopamine action on metabolism depending on genetic heterogeneity), the DZD is investigating the effect of a dopamine agonist (drug) on weight in connection with a genetic polymorphism. DZD animal studies show that dopamine neurons are important targets for the metabolic hormone insulin.
Interaction of the maternal metabolism with the brain development in the human fetus
Studies show an interaction of the maternal metabolism with the autonomic nervous system of the human fetus and brain development. The DZD conducted a comparative study with 52 pregnant women without gestational diabetes but with and without a family history of type 2 diabetes. In fetuses of mothers with hereditary predisposition, fetal brain activity was similar to that in the presence of gestational diabetes. In addition, maternal family history of diabetes is also associated with fetal postprandial brain activity. This suggests that genetic and/or epigenetic factors modulate the postprandial brain response of the developing fetus.
Effects of insulin resistance in the brain
A recent study by the DZD shows that the insulin action in the brain has an influence on body weight and fat distribution. If the brain reacts sensitively to the hormone, a lifestyle intervention will result in significant weight loss and a reduction in unhealthy abdominal fat. If the brain reacts only slightly or not at all to insulin, people only lose some weight at the beginning of the intervention and then regain weight. Visceral fat also continues to increase in the long term.
The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metabolism (2021), DOI: https://doi.org/10.1016/j.cmet.2021.01.015
Central nervous pathways of insulin action in the control of metabolism and food intake. Lancet Diabetes Endocrinol. (2020), DOI: 10.1016/S2213-8587(20)30113-3
Brain insulin sensitivity is linked to adiposity and body fat distribution. Nature Communications (2020), DOI: doi.org/10.1038/s41467-020-15686-y
Fluorescent blood-brain barrier tracing shows intact leptin transport in obese mice. International Journal of Obesity (2019), DOI: 10.1038/s41366-018-0221-z
Insulin action in the hypothalamus increases second phase insulin secretion in humans. Neuroendocrinology (2019), DOI: 10.1159/000504551
The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons. Cell Reports (2019), DOI: 10.1016/j.celrep.2019.05.037
Prof. Dr. Hubert Preißl, Head DZD Academy Brain
Talk at the 10th anniversary celebration of the DZD on June 24, 2019 in Berlin (in English).
Members of the Academy
Jens Brüning, Köln
Andreas Fritsche, IDM
Cristina García Cáceres, HMGU
André Kleinridders, DIfE
Stephanie Kullmann, IDM
Rachel Lippert, DIfE
Sebastian Meyhöfer, Lübeck
Soyoung Park, DIfE
Paul Pfluger, HMGU
Hubert Preißl, IDM
Sophie Stecolorum, Köln
Marc Tittgemeyer, Köln
Eckhard Wolf, LMU