For many obese people gaining weight is a vicious cycle. Scientists at the MDC have now uncovered a contributing factor: genetic variants linked to obesity cause the brain to produce too much of a protein called Cadm1. The result is a disruption in the regulation of body weight and changes in behavior and metabolism, as reported by Matthew Poy and his colleagues in Nature Neuroscience.
It's hard to find a point of attack with diseases such as obesity, diabetes or metabolic syndrome due to their widespread effects on diverse types of cells, organs and even behavior. Most metabolic conditions either disrupt the production of insulin by cells in the pancreas or the way tissues respond to the hormone. Matthew Poy's lab at the MDC knew that a "cellular adhesion molecule" called Cadm1 influences the growth of pancreatic cells and their release of insulin. "This put Cadm1 on the map of metabolic regulation for us," Poy says.
In the current study his group carried out a thorough analysis of genetic variants commonly associated with obesity. They found that one lay near the gene encoding Cadm1 and a second in the vicinity of another cell-adhesion gene, called Cadm2. Their locations suggested that the variants might be involved in the regulation of the genes, by influencing the types of cells that used them to produce proteins or the quantities they made.
Cadm1 and Cadm2 were known to help assemble synapses, whose physical structure supports the transmission of signals in the central nervous system. That was a logical place to search for connections between the diverse symptoms of obesity and other metabolic diseases. Poy's lab began a series of experiments to determine whether the variants linked to obesity affected particular regions of the brain.
From neural connectivity to metabolism
For the current study, MDC postdoc Thomas Rathjen, his colleagues in Poy's group, and labs across Germany, France and the USA analyzed levels of Cadm1 and Cadm2 in ten regions of the human brain, drawing on data provided by an international consortium. A pattern emerged: people on the heavy end of the body mass index often had unusually high levels of Cadm1 in the hypothalamus and cerebellum. These regions are involved in the regulation of hormones and metabolism. A similar pattern appeared in lines of mice used as models in obesity research. The same two areas of the brain were affected, as well as the hippocampus.
If the protein truly played a role in obesity, it ought to be sensitive to diet. The scientists put mice on a low-carbohydrate diet, which generally increases animals' sensitivity to insulin and brings the amount of glucose in their blood down closer to normal levels. After 60 days on the diet, less Cadm1 was detected in the regions of the animals' brains.
Next the researchers examined a strain of mouse that lacked the Cadm1 protein throughout the entire body. Compared to mice with normal amounts of the molecule, the animals had some sort of protection against obesity. Mice that lacked Cadm1 expended more energy, were more mobile and could take up sugar more efficiently from the bloodstream. An analysis of their brain tissues revealed changes in the interplay between the excitation and inhibition of nerves in the nucleus arcuatus, a region of the hypothalamus which is known to control appetite and energy balance.
Equally interesting would be to see what would happen if you artificially raised amounts of Cadm1 in specific brain tissues. The scientists developed a line of mice in which they could switch on the Cadm1 gene uniquely in the hypothalamus. The animals were put on a "fast food" diet, and then the scientists flipped the molecular switch. Although the mice ate no more than a control group, they fattened up rapidly. The likely explanation: they weren't as active, and were expending less energy.
A recent, growing area of research
"Many other genes involved in the regulation of body weight are produced at particularly high levels in the brain," Poy says. The study adds Cadm1 to a growing list of molecular links between metabolism and the central nervous system – other connections have recently been explored in publications from the labs of Thomas Willnow, Gary Lewin, Thomas Jentsch, Carmen Birchmeier and further MDC scientists.
Poy says that most efforts to understand the interplay between the brain and metabolic processes have come fairly recently, and there is still a lot to learn. "We've been aware of links between behavior and metabolism," he says, and points to the elevated levels of Cadm1 found in the hippocampus of animal brains. This region plays a central role in memory and spatial learning, whose connections to habitual behavior might link Cadm1 to changes associated with obesity. But those connections, he says, will need to be established through future work.
- Results from the Thomas Willnow group on obesity and a protein usually found in the brain: ”
Featured image: 3D rendering the cell body of a neuron. Credit: Natalia Kononenko
Thomas Rathjen1,17, Xin Yan1,17, Natalia L Kononenko2–4, Min-Chi Ku1,5 , Kun Song1, Leiron Ferrarese1,4, Valentina Tarallo6, Dmytro Puchkov2, Gaga Kochlamazashvili2, Sebastian Brachs7, Luis Varela8, Klara Szigeti-Buck8, Chun-Xia Yi9, Sonja C Schriever9, Sudhir Gopal Tattikota1, Anne Sophie Carlo1, Mirko Moroni1, Jan Siemens10, Arnd Heuser1, Louise van der Weyden11, Andreas L Birkenfeld12,13, Thoralf Niendorf1,5,14, James F A Poulet1,4, Tamas L Horvath8,15, Matthias H Tschöp9, Matthias Heinig16, Mirko Trajkovski6, Volker Haucke2,4, Matthew N Poy1 (2017): “Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1.” Nature Neuroscience.
1Max Delbrück Center for Molecular Medicine, Berlin. 2Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin. 3CECAD Research Center, University of Cologne, Cologne. 4Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin. 5Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin. 6University of Geneva, Medical Faculty, Department of Cell Physiology and Metabolism, Centre Médical Universitaire (CMU), Geneva, Switzerland. 7Charité – Universitätsmedizin Berlin, Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Berlin. 8Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. 9Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Division of Metabolic Diseases, Technical University Munich, Munich. 10Department of Pharmacology, University of Heidelberg, Heidelberg. 11Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. 12Section of Metabolic Vascular Medicine and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Medical Clinic III, University Clinic Dresden, Dresden. 13Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK. 14Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Berlin. 15Department of Anatomy and Histology, University of Veterinary Sciences, Budapest, Hungary. 16Helmholtz Zentrum München, Institute of Computational Biology, Neuherberg.