A gene that links stressful situations with obesity, diabetes and other metabolic diseases

Weizmann Institute of Science scientists have discovered the genetic basis that is expected to double the number of type 2 diabetes patients

The increasing exposure to pressures in modern Western society takes a heavy toll: both in an increasing rate of mental disorders such as anxiety and depression, and in metabolic (metabolic) diseases such as obesity, type 2 diabetes, arteriosclerosis and more. In both cases it is a global epidemic that has been expanding in recent decades: according to data from the World Health Organization, the number of diabetes patients worldwide is expected to double in the next two decades, reaching more than 360 million people in 2030. The relationship between exposure to stressful situations and Anxious behavior and changes in eating are almost self-evident to anyone who has found themselves eating large amounts of chocolate before an important test, and is also supported by scientific studies. However, the mechanisms underlying this relationship are unknown.

Dr. Alon Chen and the members of his research group from the Department of Neurobiology at the Weizmann Institute of Science discovered that a change in the activity of a single gene in a defined area of ​​the brain increases the anxious behavior of mice, and at the same time causes changes in metabolism - so that the mice develop symptoms typical of type 2 diabetes. The research findings are published this week In the online edition of the scientific journal "Records of the American Academy of Sciences" (PNAS).

The response to stressful situations encompasses all the body's systems, which mobilize to deal with the threat in the best way possible. This response includes, among others, behavioral changes such as an increase in anxiety and concentration, as well as changes in metabolism, such as heat production and differences in food preference. To try to clarify the mechanism responsible for these phenomena, the group of scientists from the Weizmann Institute of Science asked to examine the involvement of a protein called Ucn3 (urocortin 3), which is known to be one of the factors that regulate the body's response to stressful situations. The protein is created in nerve cells at a certain site in the brain, and its production is increased in times of stress. Extensions of these nerve cells function as a kind of "fast road" in which the Ucn3 moves from its place of production to two separate places in the brain: one is the hypothalamus - a region of the brain responsible for the hormonal control of the body, and among other things, regulates the feeling of hunger and satiety. The second site monitors the behavior, and is related to the regulation of anxiety levels. In these two sites there are unique receptors that bind to Ucn3, and subsequently activate the behavioral response to stressful situations.

Weizmann Institute scientists created an advanced genetic system that allows influencing a single gene, in a precise location, and used it to increase the amount of Ucn3 produced at a specific site
in the brain. They discovered that increased production of the protein caused changes in two different systems: it increased the anxious behavior of the mice, and at the same time, caused changes in metabolism. Thus, among other things, mice that produced an excess amount of Ucn3 preferred to use sugars to produce energy, instead of utilizing fatty acids, and their metabolic rate was faster. In addition, these mice developed typical symptoms of type 2 diabetes: a decrease in muscle sensitivity to insulin, which inhibits the entry of sugar into the cells, and causes an increase in the blood sugar level. As a result, insulin production in the pancreas increased (in order to try to "compensate" for the lack of response).

"We showed that a specific change in the activity of a single gene, in a specific location in the brain, leads to a change in the metabolism of the entire body," says Dr. Chen. The mechanism discovered by the scientists, which links stressful situations at the brain level, and the development of metabolic diseases, may allow, in the future, the development of treatment methods for metabolic diseases related to stressful situations - such as obesity and type 2 diabetes - through an effect on Ucn3 or its receptor.

Research students Yael Kuperman, Orna Isler, Limor Regev, Yifat Mosari, Inbal Navon and Adi Neufeld-Cohen participated in the study, and laboratory technician Shush Gil, from the Department of Neurobiology at the Weizmann Institute of Science.