Discovery could lead to new therapies for treating Type 2 diabetes, obesity

Researchers at UT Southwestern Medical Center have identified neural pathways that increase understanding of how the brain regulates body weight, energy expenditure, and blood glucose levels - a discovery that can lead to new therapies for treating Type 2 diabetes and obesity.

The study, published in Nature Neuroscience, found that melanocortin 4 receptors (MC4Rs) expressed by neurons that control the autonomic nervous system are key in regulating glucose metabolism and energy expenditure, said senior author Dr. Joel Elmquist, Director of the Division of Hypothalamic Research, and Professor of Internal Medicine, Pharmacology, and Psychiatry.

"A number of previous studies have demonstrated that MC4Rs are key regulators of energy expenditure and glucose homeostasis, but the key neurons required to regulate these responses were unclear," said Dr. Elmquist, who holds the Carl H. Westcott Distinguished Chair in Medical Research, and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley. "In the current study, we found that expression of these receptors by neurons that control the sympathetic nervous system, seem to be key regulators of metabolism. In particular, these cells regulate blood glucose levels and the ability of white fat to become 'brown or beige' fat."

Using mouse models, the team of researchers, including co-first authors Dr. Eric Berglund, Assistant Professor in the Advanced Imaging Research Center and Pharmacology, and Dr. Tiemin Liu, a postdoctoral research fellow in Internal Medicine, deleted MC4Rs in neurons controlling the sympathetic nervous system. This manipulation lowered energy expenditure and subsequently caused obesity and diabetes in the mice. The finding demonstrates that MC4Rs are required to regulate glucose metabolism, energy expenditure, and body weight, including thermogenic responses to diet and exposure to cold. Understanding this pathway in greater detail may be a key to identifying the exact processes in which type 2 diabetes and obesity are developed independently of each other.
In 2006, Dr. Elmquist collaborated with Dr. Brad Lowell and his team at Harvard Medical School to discover that MC4Rs in other brain regions control food intake but not energy expenditure.

The American Diabetes Association lists Type 2 diabetes as the most common form of diabetes. The disease is characterized by high blood glucose levels caused by the body's lack of insulin or inability to use insulin efficiently, and obesity is one of the most common causes. Future studies by Dr. Elmquist's team will examine how melanocortin receptors may lead to the "beiging" of white adipose tissue, a process that converts white adipose to energy-burning brown adipose tissue.