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Insights into the role of the hypothalamus in obesity and T2DM

Leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60
Dr C Ronald Kahn

Researchers from the Joslin Diabetes Center have gained new insights into how obesity and type 2 diabetes can create a stress response in the brain, especially in the hypothalamus which regulates appetite and energy production, that may contribute to altering metabolism throughout the body.

"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," said Dr Andre Kleinridders, study lead author and an Investigator in the Joslin Section on Integrative Physiology and Metabolism.

In the study, reported in 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.

“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,” said Dr C Ronald Kahn, 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.

Although they used mice that were genetically engineered not to produce Hsp60, it was discovered that they also exhibited mitochondrial dysfunction in the brain which led to insulin resistance in the hypothalamus.

"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,” added Kahn. “The brain not only controls metabolism but the body's metabolism affects the brain and aspects of brain function."

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.

"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," explained 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,” said Kleinridders.

“Importantly, type 2 diabetic patients exhibited decreased expression of HSP60 in the brain, indicating that this mechanism is relevant to human disease,” the authors conclude. “These data indicate that leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60. Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states.”

The study was funded by the National Institutes of Health.

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