The findings, reported in the November 4, 2005 issue of the journal Cell, demonstrate for the first time that the neuronal pathways that help to keep body weight stable diverge at the melanocortin-4 receptor (MC4R) to regulate either food intake or energy expenditure.
This unexpected discovery helps to extend the understanding of the complex neurocircuitry behind body weight control, an endeavor that began more than a decade ago with the identification of the leptin hormone and which has been growing steadily ever since.
"Maintaining a stable body weight is a delicate balancing act between the amount of food eaten versus the number of calories burned," says Bradford B. Lowell, MD, PhD, of BIDMC's department of endocrinology, diabetes and metabolism who, together with Joel K. Elmquist, DVM, PhD, served as co-senior author of the study. "The brain controls both food intake and calories expended with the purpose of keeping body weight stable. When something goes wrong with this process, obesity results. The findings of this new research provide us with more precise information about the neuronal pathways regulating this balance."
Body weight maintenance can be viewed as an intricate process made up of three basic elements, say Lowell and Elmquist, both of whom are also associate professors of medicine at Harvard Medical School (HMS). In the first, the brain receives sensory input from the body (including information provided by circulating hormones such as leptin and ghrelin and from fuels such as glucose and fatty acids). It then integrates this sensory information with cues it has received from the outside world (such as aromas and other enticements) along with information gathered from the organism's emotional state.
Finally, they explain, the brain makes appropriate alterations in food intake and energy expenditure in order to maintain "energy balance" and prevent obesity. Among the proteins that have been identified as being critical to this process is the receptor protein MC4R.
"Scientists have known that by activating MC4Rs, body weight can be reduced," explains the study's lead author Nina Balthasar, PhD, a member of Lowell's laboratory and an instructor in medicine at HMS. In fact, she adds, research has shown that when all MC4 receptors are removed in gene knockout mice, the animals become morbidly obese. This process is important in people as well, because humans with defective MC4 receptors also become obese.
In this new study Balthasar and her coauthors set out to identify the exact groups of neurons responsible for producing these important effects of MC4 receptors.
"We knew that MC4Rs were located throughout the brain and that they were responsible for a number of functions. What we didn't know was whether MC4Rs in one specific region regulated energy balance, or whether this function was distributed throughout the brain." Furthermore, she adds, if indeed more than one area of the brain were involved in maintaining stable body weight, the authors wanted to learn whether the control of food intake and energy expenditure were tracking together, or whether there was a divergence such that one MC4R site was controlling food intake and another site was controlling energy expenditure.
Using a novel genetic engineering technique, the scientists generated MC4R deficient mice in which the MC4R could be selectively reactivated. This allowed them to manipulate gene expression in a small subpopulation of neurons. With this specialized technique, Balthasar discovered that the receptors in two specific areas of the brain - the paraventricular hypothalamus (PVH) and a subpopulation of the amygdala - were controlling food intake, while MC4Rs on neurons elsewhere in the brain were controlling energy expenditure.
"When the MC4R was reactivated only in the PVH/amygdala region, 60 percent of obesity was prevented," she explains. "This suggested to us that the MC4Rs in the PVH and/or amygdala were key MC4Rs in the regulation of body weight."
The authors went on to discover functional divergence at the MC4R in the control of food intake or energy homeostasis - a novel concept placing the MC4R in the neuronal "effector arm" that splits to control food intake and energy expenditure. In other words, says Balthasar, they learned that the food intake side and the energy expenditure side of the energy balance "seesaw" are separately regulated by MC4Rs in different areas of the brain.
"Ultimately, these new findings help to refine our understanding of the neuronal logic behind body weight," the authors conclude. "And in our present climate in which the incidence of obesity and attendant health problems is rapidly increasing, every bit of new information is key."
In addition to Balthasar, Lowell and Elmquist, study coauthors include BIDMC investigators Louise T. Dalgaard, PhD, Charlotte E. Lee, Jia Yu, Todd Williams, PhD, Manuel Ferreira, MD, PhD, Vinsee Tang, Robert A. McGovern, Christopher D. Kenny, Lauryn M. Christiansen, Elizabeth Edelstein, Brian Choi, Olivier Boss, PhD, Carl Aschkenasi, MD, and Chen-yu Zhang, PhD; Hisauki Funahashi, PhD, and Toshiro Kishi, MD, of BIDMC and Shimane University School of Medicine, Japan; and Kathleen Mountjoy, PhD, of the University of Auckland, New Zealand.
This study was supported in part by grants from the National Institutes of Health and Takeda Pharmaceutical Company, Ltd.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks fourth in National Institutes of funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.