Joslin Boosts Insight into Role of Brain Stress in Obesity and Type 2 Diabetes Development

Correcting Stress Response in the Brain May Lead the Way to Improve Metabolic Function and Weight Control


  • newswise-fullscreen Joslin Boosts Insight into Role of Brain Stress in Obesity and Type 2 Diabetes Development

    Credit: John Soares

    C. Ronald Kahn, M.D., is Chief Academic Officer at Joslin Diabetes Center. Dr. Kahn is co-head of the section on Integrative Physiology & Metabolism and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.

Newswise — BOSTON – October 1, 2013 -- Joslin researchers have gained new insights into how obesity and type 2 diabetes can create a stress response in the brain, especially in the hypothalamus (the brain region that regulates appetite and energy production), that may contribute to altering metabolism throughout the body. The findings are reported in the October issue of the Journal of Clinical Investigation.

The researchers investigated the role of the molecular chaperone heat shock protein 60 (Hsp60) in hypothalamic insulin resistance and mitochondrial dysfunction in type 2 diabetes. Hsp60 is a stress response protein that protects the mitochondria, the "power plants" of the cell that produce energy. They found that in type 2 diabetes and obesity, the level of Hsp60 goes down, making mitochondria less efficient and leading to insulin resistance in the brain and altered metabolism throughout the body. In the study, mice genetically engineered not to produce Hsp60 also exhibited mitochondrial dysfunction in the brain which led to insulin resistance in the hypothalamus. "This is the first time a study has shown that mitochondrial dysfunction can cause insulin resistance in the hypothalamus and how this can lead to altered metabolism throughout the body," says Andre Kleinridders, Ph.D., study lead author and an Investigator in the Joslin Section on Integrative Physiology and Metabolism.

The investigators also showed that leptin, the hormone produced by fat cells that regulates appetite, is one of the key factors that regulate Hsp60 expression in the hypothalamus and that in obesity this regulation is lost. “These findings link obesity and the fat cell hormone leptin to the process of altered Hsp60 levels in the brain and this appears to start the ball rolling toward altering metabolism in other tissues of the body as well,” says C. Ronald Kahn, M.D., study senior author and Joslin Chief Academic Officer and Head of the Section on Integrative Physiology and Metabolism, and Mary K. Iacocca Professor of Medicine at Harvard Medical School.

"It's a vicious cycle: people become obese, obesity disturbs the way the hypothalamus responds to stress, which makes people more likely to stay obese and become diabetic. The brain not only controls metabolism but the body's metabolism affects the brain and aspects of brain function," says Dr. Kahn.

Fortunately, these negative effects are not permanent. "Hsp60 deficiency is an acquired defect that can be reversed by weight loss. Also, there is potential to develop drugs that boost Hsp60 levels and improve leptin sensitivity, which could help obese people lose weight. There is definitely strong interest in this area," says Dr. Kahn.

Joslin researchers are also investigating how mitrochondrial dysfunction and insulin resistance affect the brain as it ages. “Mitochondrial dysfunction and insulin resistance in the brain are associated with neurodegenerative diseases. If we could treat mitochondrial dysfunction in the brain, it could increase cognitive performance," says Dr. Kleinridders.

The study was funded by the National Institutes of Health.

About Joslin Diabetes Center

Joslin Diabetes Center, based in Boston, Massachusetts, undertakes diabetes research, clinical care, education and health and wellness programs on a global scale. Joslin is dedicated to ensuring that people with diabetes live long, healthy lives and offers real progress in preventing and curing diabetes Joslin is an independent, nonprofit institution affiliated with Harvard Medical School, and is recognized worldwide for driving innovative solutions in diabetes prevention, research, education, and care.

Our mission is to prevent, treat and cure diabetes. Our vision is a world free of diabetes and its complications. For more information, visit www.joslin.org.

About Joslin Research

Joslin Research comprises the most comprehensive and productive effort in diabetes research under one roof anywhere in the world. With 30‐plus faculty‐level investigators, Joslin researchers focus on unraveling the biological, biochemical and genetic processes that underlie the development of type 1 and type 2 diabetes and related complications.

Joslin research is highly innovative and imaginative, employing the newest tools in genetics, genomics and proteomics to identify abnormalities that may play a role in the development of diabetes and its complications. Joslin Clinic patients, and others with diabetes, have the option of participating in clinical trials at Joslin to help translate basic research into treatment innovations.

Joslin has one of the largest diabetes training programs in the world, educating 150 M.D. and Ph.D. researchers each year, many of whom go on to head diabetes initiatives at leading institutions all over the globe. For more information, visit www.joslinresearch.org.

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