How Obesity, Type 2 Diabetes Affect the Brain

In a new study, Harvard Medical School researchers have found that obesity and type 2 diabetes can create a stress response in the brain, especially in the hypothalamus, the region of the brain that regulates appetite and energy production.

The findings reveal that, in type 2 diabetes and obesity, the level of Hsp60 goes down, which makes mitochondria less efficient and leads to insulin resistance in the brain and altered metabolism throughout the body.

Researchers studied mice that were genetically engineered not to produce Hsp60, and found the animals exhibited mitochondrial dysfunction in the brain, which led to insulin resistance in the hypothalamus. The investigators also determined that leptin—the hormone produced by fat cells that regulate appetite—is one of the primary factors that regulate Hsp60 expression in the hypothalamus; a regulation that does not occurin the obese.

The findings establish a connection between obesity and leptin and the process of altered Hsp60 levels in the brain, which seems to be the first step toward altering metabolism in other body tissues as well, says C. Ronald Kahn, MD, senior study author and professor of medicine at Harvard Medical School.

“Diabetes and obesity are associated with inflammation and stress responses in a number of tissues,” says Kahn, who is also head of the section on integrative physiology and metabolism and chief academic officer at Joslin Medical Center. “This shows that the same process may be affecting the hypothalamus, which is critical in appetite regulation and energy balance, as well as control of metabolism in other ways.”

While “we do not yet know how to reduce these effects in the brain,” the findings indicate potential for the development of an intervention or treatment to impede this mechanism, says Kahn, noting that “this is something we are studying currently.

“We believe this is a pathway that is worth developing interventions or treatments for,” he says, “and this work is ongoing.”

The complete study is published in the October issue of The Journal of Clinical Investigation.

—Mark McGraw

Reference:

Kleinridders A, Lauritzen H, Siegfried U, et al. Leptin regulation of Hsp60 impacts hypothalamic insulin signaling. J Clin Invest. 2013. doi:10.1172/JCI67615.