June 3, 2009 In investigating the complex neurocircuitry behind weight gain and glucose control, scientists have known that the hormone leptin plays a key role in the process. But within the myriad twists and turns of the brain's intricate landscape, the exact pathways that the hormone travels to exert its influence have remained a mystery.
Now, a study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) sheds further light on the subject. Reported in tomorrow's issue of the journal Cell Metabolism, the findings demonstrate that when leptin sensitivity is restored to a tiny area of POMC neurons in the brain's hypothalamus, a group of mice deficient in the leptin-receptor are cured of severe diabetes – and also spontaneously double their activity levels – independent of any change in weight or eating habits.
"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," explains Christian Bjorbaek, PhD, an investigator in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Associate Professor of Medicine at Harvard Medical School. "We know that the majority of humans with Type 2 diabetes are obese and that weight loss can often ameliorate the disease. However, in many cases, it's difficult for these individuals to lose weight and can keep weight off. If, as these findings suggest, there is a system in the brain that can control blood-glucose directly, it offers hope for the identification of novel anti-diabetic drug targets."
First identified in 1994 as an appetite and weight-regulation hormone, leptin plays a key role in energy homeostasis through its effects on the central nervous system. Over the years, investigators have pinpointed a region of the brain's hypothalamus known as the arcuate nucleus (ARC) as one key area where leptin exerts its influence, and within the ARC, they have identified two types of leptin-responsive neurons, the Agouti-related peptide (AgRP) neurons, which stimulate appetite and the pro-opiomelanocortin (POMC) neurons, which curb appetite.
"Still other studies had indicated that, by way of the ARC, leptin also had a function in both blood-sugar control and in activity levels," notes Bjorbaek. "We hypothesized that, in both cases, the POMC neurons were involved."
To test their hypothesis, the scientists studied a group of leptin-receptor-deficient laboratory mice. "The animals were severely obese and profoundly diabetic," he explains. "Using Cre-Lox technology we were able to genetically and selectively re-express leptin receptors only in the POMC neurons. When leptin receptor activity was restored to just this very small group of neurons, the mice began eating about 30 percent fewer calories and lost a modest amount of weight." And, he adds, even more dramatically, the animals' blood sugar levels returned to normal independent of any change in weight or eating habits, and their activity levels spontaneously doubled.
While more research is needed to explain the mechanisms at play, it may be that the POMC neurons reduce blood glucose by regulating key organs such as the liver or muscle tissue. "Normally, the liver is critical for increasing glucose production between meals in order to provide fuel for the brain, while skeletal muscle is important for the removal of glucose from the blood immediately after a meal," he notes. In this case, however, the POMC neurons may be decreasing glucose release into the blood by the liver and/or increasing glucose uptake from the blood into muscle.
"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," explains Bjorbaek. "Furthermore, our finding that the mice had greatly increased activity levels despite still being highly overweight provides hope that POMC neurons and downstream neuronal systems might eventually be tapped to develop drugs that increase the will to voluntarily exercise in individuals who are overweight or obese."
Study coauthors include BIDMC researchers Lihong Huo (first author), Kevin Gamber, Sarah Greeley, Jose Silva and Nicholas Huntoon and Xing-Hong Leng of Baylor College of Medicine, Houston, Texas.
This study was funded by grants from 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.
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