Scientists unravel brain-hormone circuit that helps police diabetes, female fertility

"Many people, and even many physicians, think you develop diabetes that is solely secondary to obesity," said Dr. Joel Elmquist, professor of internal medicine and pharmacology at UT Southwestern and senior author of the study, which appears online and in the current issue of Cell Metabolism. "Our findings indicate that is not necessarily the case, at least in mice. We can make the animals very diabetic without obesity, suggesting that there may be a circuit or path of resistance to these signals in the brain that helps explain the powerful anti-diabetic actions of leptin."

Additionally, the study indicates that a person may not have to be obese to develop type 2 diabetes, Dr. Elmquist added.

Prior research by Dr. Roger Unger, professor of internal medicine at UT Southwestern, has shown that a single injection of leptin, a hormone produced by the body's fat cells, can restore terminally ill rodents with type 1 diabetes to full health. The underlying cellular mechanisms that caused that effect, however, have been elusive.

Although diabetes and obesity often go hand in hand, Dr. Elmquist said the new findings indicate that a group of brain cells called pro-opiomelanocortin, or POMC, neurons help regulate glucose and insulin independent of food intake and body weight. POMC neurons, found in the hypothalamus, a small region of the brain, previously have been shown to play an important role in suppressing appetite and inducing weight loss.

In the current study, the researchers genetically engineered mice to lack both leptin and insulin receptors in their POMC neurons. Both receptors remained intact in all other cell types and tissues, including the liver and ovaries.

Prior research has shown that deleting the leptin receptor alone from POMC neurons results in mild obesity and has little effect on the regulation of blood sugar levels, while deleting only the insulin receptor has no noticeable impact on body weight or blood sugar regulation.

The researchers found, however, that when they removed both receptors from these particular neurons the mice displayed systemic insulin resistance and became severely diabetic but not obese. Dr. Elmquist said the findings suggest that leptin and insulin -- when acting on these neurons in the brain -- are both necessary and can compensate for each other if there's a shortage of one.

"There seems to be what I call a functional redundancy in these neurons as it relates to blood sugar regulation," said Dr. Elmquist. "We don't know if the same neurons respond to both leptin and insulin, but it is clear that functionally leptin can compensate for a lack of insulin and vice versa."

The researchers also found that female mice that lacked the hormone receptors in POMC neurons had difficulty reproducing and produced smaller litters than mice lacking just one of the receptors. This is due in part to the fact that the females lacking both receptors had extremely high levels of androgens, the researchers speculate. The most well-known androgen is the male sex hormone testosterone.

"Reproductive endocrinology isn't my area of expertise, but these findings were nonetheless completely unexpected," Dr. Elmquist said. "We believe this may be one of the first genetic models of polycystic ovary syndrome."

Polycystic ovary syndrome, or PCOS, is a metabolic disorder characterized by abnormal hormone levels. It is often associated with a wide range of afflictions in women, ranging from obesity and excessive facial hair to more severe disorders, such as infertility, diabetes and heart disease.

Dr. Elmquist said one of his goals is to understand better how these hypothalamic POMC neurons control glucose production in the liver.

The study is also part of UT Southwestern's Task Force for Obesity Research. In 2007, the multidisciplinary group received a $22 million grant from the National Institutes of Health to enhance its efforts to attack obesity from every angle. The award is one of nine interdisciplinary research consortia sponsored by the NIH Roadmap for Medical Research, a series of initiatives designed to transform the nation's medical research capabilities. The UT Southwestern group is the only one focused on obesity.

Other UT Southwestern researchers involved in the study were Drs. Carol Elias and Roberto Coppari, assistant professors of internal medicine; Dr. Jeffrey Zigman, assistant professor of internal medicine and psychiatry; Drs. Makoto Fukuda and Yong Xu, instructors of internal medicine; Dr. Kevin Williams, assistant instructor of internal medicine; Drs. Eric Berglund, William Holland and Jen-Chieh Chuang, postdoctoral research fellows in internal medicine; Danielle Lauzon, research assistant; Charlotte Lee, senior research scientist; Dr. James Richardson, professor of pathology, molecular biology and plastic surgery; Dr. Philipp Scherer, professor of internal medicine and cell biology; Dr. Jennifer Hill, lead author and former instructor of internal medicine; Dr. You-Ree Cho, former postdoctoral research fellow in internal medicine; and Michelle Choi, former research assistant in internal medicine. Researchers from the Albert Einstein College of Medicine, Beth Israel Deaconess Medical Center and the University of Cologne in Germany, also contributed to the work.

The study was funded by the American Diabetes Association, the Richard and Susan Smith Family Foundation, the NIH and DFG, a German research foundation.