Today obesity is epidemic in the industrialized world, causing disturbances in blood levels of insulin, sugar, and blood fats that lead to high blood pressure, type-2 (adult onset) diabetes, and fatty liver, which in turn conspire to cause cardiovascular disorders, the leading cause of premature death in the Western world. Obesity is also associated with an increased risk of various types of cancer. Children and adolescents are becoming more and more obese and are also developing these complications. In the U.S. this has meant that the next and coming generations may be the first in modern history to be sicker and a shorter lifespan than their parents, which is considered a medical disaster.
Today we do not understand at the molecular level how obesity causes diabetes, fatty liver, and blood-fat disturbances, and we therefore also lack effective methods of treatment to prevent or cure these complications. A research team led by Helena Edlund at Umeå University is now publishing in the journal Cell Metabolism a breakthrough in our understanding of the role of obesity in this connection. Her associate at Umeå University is post-doctoral fellow Pär Stenberg, and other co-authors belong to Dr. Michael D. Walker’s team at the Weizman Institute of Science, Israel.
Obesity leads to heightened levels of free fatty acids that are stored and converted to fats in various tissues. A recently discovered surface receptor for free fatty acids, called GPR40, is in mice present solely in the insulin-producing beta cells. Mice, like humans, that eat a diet rich in calories gain weight quickly and experience disturbances in their blood levels of insulin, sugar, and fats, and they develop fatty liver and diabetes. The findings of the Umeå team show that mice that lack GPR40 receptors are healthy and experience normal weight gain on a calorie-rich diet. These mice are, however, protected from the complications and diseases that obesity provokes. The findings thus indicate that obesity leads to increased levels of free fatty acids that stimulate the secretion of insulin via GPR40 receptors, which in turn contributes to disease development. By inactivating GPR40 function the animals are protected from these diseases. This theory is supported by the finding that mice with an increased number of GPR40 receptors on their beta cells develop diabetes. GPR40 belongs to the class of receptors targeted by most drugs. The receptors also occur on human beta cells, and therefore substances that block these receptors are prime candidates as drugs for preventing or curing diabetes and other complications of obesity.