REHOVOT, ISRAEL—April 19, 2010—The constant stress that many are exposed to in our modern society may be taking aheavy toll: Anxiety disorders and depression, as well as metabolic(substance exchange) disorders, including obesity, type 2 diabetes, andarteriosclerosis, have all been linked to stress. These problems are reaching epidemic proportions: Diabetes alone is expected to affect some 360 million people worldwide by the year 2030. While anyone who has ever gorged on chocolate before an important exam recognizes the tie between stress, changes in appetite, and anxiety-related behavior, the connection has lately been borne out by science, although the exactreasons for the connection aren't crystal clear. Dr. Alon Chen of the Weizmann Institute's Department of Neurobiology and his research team have now discovered that changes in the activity of a single gene in the brain not only cause mice to exhibit anxious behavior, but also lead to metabolic changes that cause them to develop symptoms associated with type 2 diabetes. These findings were published online this week in the Proceedings of the National Academy of Sciences (PNAS).
All of the body's systems are involved in the stress response, whichevolved to deal with threats and danger. Behavioral changes tied tostress include heightened anxiety and concentration, while changes inthe body include heat generation, changes in the metabolism of varioussubstances, and even changes in food preferences. What ties all of thesethings together? The Weizmann team suspected that a protein known asUrocortin-3 (Ucn3) was involved. This protein is produced in certainbrain cells—especially in times of stress—and it's known to play a rolein regulating the body's stress response. These nerve cells haveextensions that act as "highways" that speed Ucn3 on to two other sitesin the brain: One, in the hypothalamus—the brain's center for hormonalregulation of basic bodily functions—oversees, among other things,substance exchange and feelings of hunger and satiety; the other isinvolved in regulating behavior, including levels of anxiety. Nervecells in both these areas have special receptors for Ucn3 on theirsurfaces, and the protein binds to these receptors to initiate thestress response.
The researchers developed a new, finely tuned method for influencingthe activity of a single gene in one area in the brain, using it toincrease the amounts of Ucn3 produced in just that location. They foundthat heightened levels of the protein produced two different effects:The anxiety-related behavior of the mice increased, and their bodiesunderwent metabolic changes. With excess Ucn3, their bodies burned moresugar and fewer fatty acids, and their metabolic rates sped up. Thesemice began to show signs of the first stages of type 2 diabetes: A dropin muscle sensitivity to insulin delayed sugar uptake by the cells,resulting in raised sugar levels in the blood. Their pancreases thenproduced extra insulin to make up for the perceived deficit.
"We showed that the actions of a single gene in just one part of thebrain can have profound effects on the metabolism of the whole body,"says Dr. Chen. This mechanism, which appears to be a smoking gun tyingstress levels to metabolic disease, might, in the future, point the waytoward the treatment or prevention of a number of stress-relateddiseases.
Participating in the research were research students Yael Kuperman,Orna Issler, Limor Regev, Ifat Musseri, Inbal Navon, and AdiNeufeld-Cohen, along with Shosh Gil, all of the Weizmann Institute'sDepartment of Neurobiology.
Dr. Alon Chen’s research is supported by the Nella and LeonBenoziyo Center for Neurosciences; the Carl and Micaela Einhorn-DominicBrain Research Institute; the Croscill Home Fashions Charitable Trust;the Irwin Green Alzheimer’s Research Fund; Gerhard and Hannah Bacharach,Fort Lee, NJ; Mark Besen and the Pratt Foundation, Australia; Robertoand Renata Ruhman, Sao Paulo, Brazil; and Barry Wolfe, Woodland Hills,CA. Dr. Chen is the incumbent of the Philip Harris and Gerald RonsonCareer Development Chair.
