Role of Brain Stress in Obesity and Type 2 Diabetes

Joslin Diabetes Center 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 were 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 researchers 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, PhD, lead study 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 regulates Hsp60 expression in the hypothalamus and that this regulation is lost with obesity. “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, MD, senior study author, Joslin chief academic officer and head of the section on integrative physiology and metabolism, and the 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,” Kahn notes.

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

Source: Joslin Diabetes Center

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