DISCOVERIES
Hormone Enlivens Obese Mice, Prevents Diabetes
Can a single hormone, acting on a tiny region of the brain, normalize blood sugar levels and increase physical activity in diabetic and obese patients? A new study from HMS and Beth Israel Deaconess Medical Center, published June 3 in Cell Metabolism, has found that leptin, a hormone famous for its ability to curb appetite, does exactly that—at least in mice.
“This discovery suggests a new therapeutic pathway for drugs to treat insulin-resistant diabetes in humans with severe obesity and possibly even to stimulate their urge to exercise,” said Christian Bjørbæk, senior author of the study and an HMS associate professor of medicine at BID. The research was led by first author and BID research fellow Lihong Huo.
The scientists began by measuring the appetite and body weight of mice whose neurons were genetically deficient in receptors for leptin. Since leptin activity is needed in the brain to regulate body weight and blood glucose, these mice were, as expected, extremely obese, hypoactive and severely diabetic.
“The fact that normal glucose levels were restored independent of food or weight changes is important because it suggests that it is possible to normalize blood glucose even without weight loss.” —Christian Bjørbæk |
The researchers tested the effect of genetically reactivating leptin receptors, using a technique called Cre-Lox, in a specific group of brain cells known as the pro-opiomelanocortin (POMC) neurons. When leptin activity was restored only to these few neurons, the mice became slightly less obese. More importantly, they also became twice as physically active, and their blood glucose decreased to normal levels. So replenishing leptin activity in the POMC neurons, although it did not cure obesity, spurred the mice to exercise more and effectively prevented diabetes.
The POMC neurons reside in the arcuate nucleus (ARC) of the hypothalamus, a region of the brain shown in past studies to regulate appetite. Until this study, the exact neurons involved in glucose regulation and physical activity were unknown, and more research is still needed to determine the specific mechanisms at work.
“The fact that normal glucose levels were restored independent of food or weight changes is important because it suggests that it is possible to normalize blood glucose even without weight loss,” said Bjørbæk. These findings may offer potential targets for future drugs that alleviate diabetes or increase the will to exercise in obese patients.
Students may contact Christian Bjørbæk at cbjorbae@bidmc.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The American Diabetes Association, the Richard and Susan Smith Family Foundation Pinnacle Program Project, the National Institutes of Health, the Endocrine Society, and the Boston Obesity Nutrition Research Center; the content of the work is the responsibility solely of the authors.