Diabetes and the Hypothalamus: A Brain-Body Connection

Q: What led you to suspect that inflammation of the hypothalamus might contribute to aging?

A: "We first found that chronic overeating triggers inflammation that leads to obesity and diabetes," says Dr. Cai. "Since we knew that inflammation is also involved with aging, we suspected that inflammation of the hypothalamus might play a role—which was indeed the case, at least in mice.

"We also found that when we injected GnRH [gonadotropin-releasing hormone]

This article originally appeared in the spring/summer 2014 issue of the Albert Einstein Diabetes Research Center Newsletter. For most of the last century, diabetes research has focused mainly on the pancreas, liver and fat. But research by Einstein’s Dr. Dongsheng Cai shows that the brain—specifically the region known as the hypothalamus—plays a crucial role in determining whether we develop diabetes. The hypothalamus performs essential roles in the body, such as controlling body temperature, hunger and thirst. "We have been studying whether some types of hypothalamic changes might be important for a network of disorders known as metabolic syndrome [involving obesity, prediabetes and hypertension] and even aging," says Dr. Cai, a professor of molecular pharmacology at Einstein.

Dr. Cai hypothesized that an inflammatory reaction in the hypothalamus might cause metabolic syndrome. He knew that overeating can chronically inflame certain tissues and lead to insulin resistance—an early step in type 2 diabetes. In the mid-1990s scientists discovered that leptin, a protein produced by fat cells, travels to the hypothalamus to help regulate food intake. Dr. Cai suspected that inflammation of the hypothalamus—the brain’s "master regulator"—might be contributing to obesity and diabetes.

Dr. Cai and his team found that inflammation of the hypothalamus is linked to obesity.

He and his team zeroed in on nuclear factor kB (NF-kB), a protein complex found in most types of animal cells. Inflammatory reactions occur in human cells via a signaling pathway involving NF-kB and an enzyme called IKK-β. Dr. Cai found that the IKK-β/NF-kB pathway is also present in the hypothalamic neurons of mice. He then showed that a high-fat diet triggers this inflammatory pathway in the hypothalamus. And interrupting this pathway—by knocking out the gene for IKK-β—not only suppressed inflammation in hypothalamic neurons but also stopped the animals from overeating and becoming obese or diabetic. Digging deeper, Dr. Cai recently showed that aging—independent of a high-fat diet—also causes inflammation by activating the IKK-β/NF-kB pathway in the hypothalamus. By interrupting this pathway in the hypothalamus of animals, Dr. Cai was able to extend their life span.

Together, these discoveries place hypothalamic inflammation at the center of obesity, diabetes and aging. They point to a wholly new approach to controlling obesity and, possibly, aging-related disorders as well, with the potential to improve the lives of many people. That’s precisely what Dr. Cai wants to do. Growing up in rural China, where disease was common and doctors scarce, Dr. Cai vowed to become a physician so he could help his community. Later, he realized that he could have a broader impact by discovering better treatments for disease, so he decided to become a researcher. Dr. Cai earned M.D. and Ph.D. degrees in China and then relocated to the United States, which he considered the best place to hone his investigative skills. "I’m not biased toward this or that country," he explains. "I'm more of an internationalist. I think of the whole world as one family."

Dr. Cai joined Einstein in 2009. His work is currently funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging and the National Heart, Lung and Blood Institute, and by an American Diabetes Association research award.