'In our present climate in which the incidence of obesity and attendant health problems is rapidly increasing, every bit of new information is key.'

Their findings are published in the November 4, 2005, issue of the journal Cell.

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.

"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. Both are associate professors of medicine at Harvard Medical School (HMS).

"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," Dr. Lowell explains. "The findings of this new research provide us with more precise information about the neuronal pathways regulating this balance."

Defective MC4 Receptors

The intricate process of body weight maintenance consists of three basic elements, say Lowell and Elmquist. In the first, the brain receives sensory input from the body, including information provided by circulating hormones, such as leptin and ghrelin, and from such fuels as glucose and fatty acids.

The brain then integrates this sensory information with cues it has received from the outside world -- such as aromas and other enticements -- along with information relevant to the organism's emotional state.

Finally, 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 lead author Nina Balthasar, PhD, a member of Lowell's laboratory and an instructor in medicine at HMS.

In earlier mouse studies, when all MC4 receptors were removed, the animals became morbidly obese, Balthasar notes. This process is important in people as well; humans with defective MC4 receptors also become obese.

Different Areas of the Brain

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," says Balthasar. "What we didn't know was whether MC4Rs in one specific region regulated energy balance, or whether this function was distributed throughout the brain."

If imore 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," Balthasar reports. "This suggested to us that the MC4Rs in the PVH and/or amygdala were key MC4Rs in the regulation of body weight."

Separate Regulation

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."