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Sugar addiction: Discovery of a brain sugar switch

August 12, 2016

Researchers at Technical University of Munich discovered that our brain actively takes sugar from the blood. Prior to this, researchers around the world had assumed that this was a purely passive process. An international team led by diabetes expert Matthias Tschöp reported in the journal 'Cell' that transportation of sugar into the brain is regulated by so-called glia cells that react to hormones such as insulin or leptin; previously it was thought that this was only possible for neurons.

The rapid rise in obesity and the associated spread of type 2 diabetes represent an enormous challenge for our society. No efficient and safe medicines to prevent or stop this development are available. The failure to develop adequate treatments is thought to be primarily due to the fact that the molecular machinery controlling systemic metabolism still remains mostly unknown.

Metabolic Control: Fuel for the headquarters

Matthias Tschöp of the Chair for Metabolic Diseases at TUM and Director of the Division of Metabolic Diseases and also of the Helmholtz Diabetes Center (HDC) at Helmholtz Zentrum München, is investigating how control centers in the brain remotely control our metabolism in order to adjust optimally to our environment. The brain has the highest sugar consumption of all organs and also controls for example hunger feelings. "We therefore suspected that a process as important as providing the brain with sufficient sugar was unlikely to be completely random," so Dr. Cristina García-Cáceres, neurobiologist at the HDC and the study's lead author. "We were misled by the fact that nerve cells apparently did not control this process and therefore first thought it to occur passively. Then we had the idea that glia cells such as astrocytes*, which had long been misunderstood as less important 'support cells', might have something to do with transporting sugar into the brain."

The scientists therefore first examined the activity of insulin receptors on the surface of astrocytes, molecular structures which respond to insulin to influence cell metabolism. Here they found that if this receptor was missing on certain astrocytes the result was less activity in neurons that curb food uptake (proopiomelanocortin neurons).

At the same time, adaption of metabolism to challenges like sugar intake became impaired. With the help of advanced imaging technologies such as positron emission tomography, the scientists were able to show that hormones such as insulin and leptin act specifically on 'support' glia cells to regulate sugar intake into the brain, like a 'sugar switch'. Without insulin receptors, astrocytes became less efficient in transporting glucose into the brain, particularly in the area of the satiety centers, which are located in the hypothalamus.

A paradigm shift

"Our results showed for the first time that essential metabolic and behavioral processes are not regulated via neuronal cells alone and that other cell types in the brain, such as astrocytes, play a crucial role," explains study leader Matthias Tschöp, who also heads the drug discovery division at the German Center for Diabetes Research (DZD). "This represents a paradigm shift and could help explain why it has been so difficult to find sufficiently efficient and save medicines for diabetes and obesity until now."

According to the scientists, numerous new studies will now be necessary to adjust the old model of purely neural control of food intake and metabolism with a concept where astrocytes and possibly even immune cells in the brain also play a crucial role. Once there is a better understanding of the interaction between these various cells, the idea is to find ways and substances that modulate pathways on multiple cell types to curb sugar addiction and ultimately provide better treatment to the growing number of obese and diabetic individuals. "We have a lot of work ahead of us," states García-Cáceres, "but at least now we have a better idea where to look."
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Background:
  • Astrocytes are the most common cells in the brain. One of their jobs is to form the blood-brain barrier by enclosing the blood vessels that run in the brain and selectively allowing only certain substances through to the nerve cells.

Just recently the scientists had already shown that astrocytes react to leptin, a metabolic hormone (Kim et al., 2014). This is an important factor for satiety. Because now both leptin and insulin have been shown to influence astrocytes, the researchers propose to develop a new model which, in addition to the neurons, also takes into account the astrocytes as the adjustors of the metabolism and the feeling of hunger. They hope that the more detailed view this produces will provide new perspectives for drug development.

Original Publication:

Caceres, C. et al. (2016): Astrocytic insulin signaling couples brain glucose uptake with nutrient availability, Cell, DOI: 10.1016/j.cell.2016.07.028

Technical University of Munich (TUM) is one of Europe's leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 39,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany. http://www.tum.de/en/homepage

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 Zentrum München - 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 the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. http://www.dzd-ev.de/en/index.html

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en

Technical University of Munich (TUM)

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