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.
- Thomas J. Wang, Debby Ngo, Nikolaos Psychogios, Andre Dejam, Martin G. Larson, Ramachandran S. Vasan, Anahita Ghorbani, John O’Sullivan, Susan Cheng, Eugene P. Rhee, Sumita Sinha, Elizabeth McCabe, Caroline S. Fox, Christopher J. O’Donnell, Jennifer E. Ho, Jose C. Florez, Martin Magnusson, Kerry A. Pierce, Amanda L. Souza, Yi Yu, Christian Carter, Peter E. Light, Olle Melander, Clary B. Clish, Robert E. Gerszten. 2-Aminoadipic acid is a biomarker for diabetes risk. Journal of Clinical Investigation, 2013; 123 (10): 4309 DOI: 10.1172/JCI64801
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