BreakThrough Digest Medical News |
| How ‘beige’ fat makes the pounds melt away Posted: 27 Aug 2012 09:00 PM PDT
The numbers of obese people are climbing steeply all over the world ? with obvious major consequences for their health. Due to excess food intake and a lack of physical activity, but also due to genetic factors, the risk for overweight people dying from diseases like coronary heart disease, diabetes und atherosclerosis increases. “The body’s fat reserves are actually used as a place to store energy that allows surviving lean times,” says Prof. Dr. Alexander Pfeifer, Director of the Institute of Pharmacology and Toxicology of the University of Bonn. “But nowadays, hardly anyone in the industrialized nations is exposed to such hunger phases anymore.”
A signal path boosts the burning of fat in the body Since many people ingest more energy in their diet than they can burn, many harbor dreams of a magic pill that will simply make fat melt away. Now, scientists around Prof. Pfeifer ? in collaboration with colleagues from Epileptology and from the PharmaCenter Bonn, together with the Max Planck Institute of Biochemistry in Martinsried – have discovered a signal path in the metabolism of mice that is indeed able to greatly boost combustion inside the rodents’ bodies. “Science distinguishes between three different types of fat,” reports Prof. Pfeifer. White fat is used to store energy and is found in the “problem zones” of overweight people. “Brown fat cells, however, are used as a kind of heating unit,” says the pharmacologist. “In babies, they make sure that they do not lose too much heat.” Unfortunately, adults have hardly any brown fat cells left?except for small areas at the back of their necks and along their spines. The third category ? the so-called “beige fat cells” ? are the ones the researchers are betting on. “Just like brown fat cells, they are efficient at converting energy from food into heat, and they can form from the undesirable white fat cells,” explains Prof. Pfeifer. How can white fat cells be converted into brown or beige ones? Consequently, the team’s research focused on how to turn the white fat cells into as many beige ones as possible. “The issue was finding a way to brown white fat ? of course, not in a skillet, but directly inside the body,” the University of Bonn pharmacologist summarized the problem. In a study published in 2009, the team around Prof. Pfeifer found that brown fat needs the neurotransmitter “cGMP.” And according to the new findings, this is also true for beige fat. The researchers now studied in mice where cGMP comes from and how it is regulated. These studies showed that vasodilator-stimulated phosphoprotein (VASP) plays an essential role as a switch on a signal path that slows down the formation of brown and beige fat cells. “This is why mice in which the gene for forming VASP was switched off have the more active brown and beige fat,” Prof. Pfeifer summarizes the study results. “These animals are lean and dissipate more energy.” In developing a regulator for the VASP/cGMP signaling pathway, the researchers see a potential starting point for promoting the energy- and fat-burning brown fat cells. Hope for new obesity therapies “This might even allow us to talk the white fat cells into converting to brown or beige fat,” says the University of Bonn researcher. “This might lead to a useful option for successfully treating obesity.” But this is still a long way off. So far, this signal path has been described in mice only. “We will have to see first if this is also successful in humans,” says Prof. Pfeifer, and added that this was just basic research that could open up new possibilities. ### Publication: A VASP/Rac/sGC pathway controls cGMP production in adipocytes, Science Signaling, DOI: 10.1126/scisignal.2002867 Contact: Contact: Profesor Dr. Alexander Pfeifer |
| Protein found to regulate red blood cell size and number Posted: 27 Aug 2012 09:00 PM PDT The adult human circulatory system contains between 20 and 30 trillion red blood cells (RBCs), the precise size and number of which can vary from person to person. Some people may have fewer, but larger RBCs, while others may have a larger number of smaller RBCs. Although these differences in size and number may seem inconsequential, they raise an important question: Just what controls these characteristics of RBCs?
By analyzing the results of genome-wide association studies (GWAS) in conjunction with experiments on mouse and human red blood cells, researchers in the lab of Whitehead Institute Founding Member Harvey Lodish have identified the protein cyclin D3 as regulating the number of cell divisions RBC progenitors undergo, which ultimately affects the resulting size and quantity of RBCs. Their findings are reported in the September 14 issue of Genes and Development. “This is one of the rare cases where we can explain a normal human-to-human variation,” says Lodish, who is also a professor of biology and bioengineering at MIT. “In a sense, it’s a window on human evolution. Why this should have happened, we have no idea, but it does.” Lodish likens cyclin D3′s role in RBCs to that of a clock. In some people, the clock triggers RBC progenitors to mature after four rounds of cell division, resulting in fewer but larger RBCs. In others it goes off after five cell division cycles, which leads to production of a greater number of smaller RBCs. In both cases, the blood usually has the same ability to carry oxygen to distant tissues. The initial hint of cyclin D3′s importance came from GWAS, genetic surveys of large numbers of people with or without a particular trait. Researchers compare the groups in an attempt to identify genetic variations. “The problem with most GWAS is that you get a bunch of potentially interesting genes, but that doesn’t tell you anything about the functional biology, so you really have to figure it out,” says Leif Ludwig, a Lodish graduate student and co-author of the Genes and Development paper. “You only know something has a role, but you don’t know how it can cause variation. This work on cyclin D3 is a really nice example of how functional follow-up on a GWAS association can really teach us something about underlying biology.” In the case of RBC size and number, a mutation affecting cyclin D3 production bubbled to the surface from the GWAS’s murky genetic data. Ludwig and co-author Vijay Sankaran then confirmed that reduced or inhibited cyclin D3 expression in mice and in human RBC progenitors caused those cells to halt cell division and mature earlier, producing larger and fewer red blood cells than mice and cells with uninhibited cyclin D3 production. As one of only a handful of studies that have successfully used GWAS to produce definitive biological results, Sankaran is excited that this work confirms the value of such genetic studies. “Can genetics teach us about biology?” asks Sankaran, also a postdoctoral researcher in the Lodish lab. “Yes! This work tells us that as genetic studies identify new genes, there will probably have been a lot of things biologists may have ignored. Genetics allows you to shine a spotlight on something interesting and then home in on it see what can be learned.” ### This work was supported by the National Institutes of Health (NIH), Boehringer Ingelheim Fonds, and Amgen, Inc. Written by Nicole Giese Rura Harvey Lodish’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology and a professor of bioengineering at Massachusetts Institute of Technology. Full Citation:
“Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number” Genes and Development, XXXXXX XX, 2012. Vijay G. Sankaran (1,2,3,8,?), Leif S. Ludwig (2,14,?), Ewa Sicinska (5,*), Jian Xu (4,6,*), Daniel E. Bauer (4,6,*), Jennifer C. Eng (1,2), Heide Christine Patterson (2,12), Ryan A. Metcalf (13), Yasodha Natkunam (13), Stuart H. Orkin (1,4,6,8), Piotr Sicinski (7,9), Eric S. Lander (1,10,11,?), and Harvey F. Lodish (1,2,11,?) 1. Broad Institute, Cambridge, Massachusetts, USA. 2. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. 3. Department of Medicine Children’s Hospital Boston, Boston, Massachusetts, USA. 4. Division of Hematology/Oncology, Children’s Hospital Boston, Boston, Massachusetts, USA. 5. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 6. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 8. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. 9. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. 10. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA. 11. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 12. Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 13. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA. 14. Institute for Chemistry and Biochemistry, Freie Universität Berlin and Charité-Universitätsmedizin Berlin, Berlin, Germany. ?These authors contributed equally to this work. *These authors contributed equally to this work. ?These authors jointly directed this work. Contact: Nicole Rura |
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