UCSF researchers have identified a novel physiological process that may contribute to obesity in middle-aged mice. The scientists suspect the same process occurs in humans and could be a factor in the weight gain that many people experience as they age. The finding, they say, suggests a possible target for therapy.
In the study, published in the February issue of Diabetes, the researchers determined that middle-aged mice expended less energy - i.e., burned fewer calories - to carry out the same physical activity—scurrying to and fro—than younger adult mice. The most dramatic findings were seen in a comparison of middle-aged and younger-adult mice genetically engineered to lack a brain cell receptor known as 5-HT(2c), which receives signals from the brain chemical serotonin; an effect, though less dramatic, was also seen in normal mice.
Traditionally, scientists have surmised that the increase in weight gain seen in middle-aged mammals, including mice and people, was due in part to declines in resting metabolic rate and physical activity levels.
However, in the study, both sets of middle-aged mice ate the same amount, had the same resting metabolic rate and had the same level of activity as their younger brethren.
The only difference, the researchers discovered, was the increased efficiency with which both groups of middle-aged mice expended energy during exercise.
In other words, they got more miles per gallon. (The increase was tightly correlated with the extent of activity and age, a fact dramatically illuminated on two graphs.)
The evidence that middle-aged mice burn fewer calories per dash across the cage - and the implication that aging people may burn fewer calories per jog down the footpath— are less than sanguine.
“This could mean that I’d burn less energy today running an 8-minute mile at a given weight than I would have 20 years ago,” says senior author Laurence Tecott, PhD, UCSF associate professor of psychiatry and a member of the UCSF Center for Neurobiology and Psychiatry.
At the same time, he says, the energy-expenditure mechanism could prove a target for therapy, offering the recipient more “bang for the buck of exercise.” A possible candidate for such a target, he says, is the serotonin 5-HT(2c) receptor.
Mice genetically engineered to lack the 5-HT(2c) serotonin receptor demonstrated the most dramatic results in the study. Young adult mutants spent their days scurrying back and forth to the feeder with a peripatetic urgency, yet despite their perpetual consumption they maintained normal body weight. It was only upon reaching middle age that they became obese. At nine to 10 months of age, they used significantly less energy during activity than either the younger mutant mice or the normal middle-aged mice.
Middle-aged normal mice, which gradually gain weight as they age, also burned less energy during activity than younger normal mice, despite eating the same moderate amount of food and maintaining the same resting metabolic rate.
The pronounced results in the mature mutant mice - the onset of obesity associated with the dramatic decrease in energy expenditure during exercise—suggest, says Tecott, that energy cost may be regulated both by aging and serotonergic signaling.
This wouldn’t necessarily suggest that mutations in the 5-HT(2c) serotonin receptor cause middle-age obesity in humans, but rather that the receptor might influence factors involved in energy expenditure and therefore could prove a target for therapy.
The amount of energy expended during physical activity is measured by the amount of oxygen that is used by the body during a specified period, in relation to weight and distant traveled. The measurement reflects the central nervous system’s response to a complex set of variables related to body composition & energy metabolism, or the buildup and breakdown of energy.
There are several mechanisms through which mutations in the 5-HT(2c) receptor could alter the input into this highly orchestrated system, says Tecott. The receptor may modulate neuro-endocrine function and/or sympathetic nervous system activity, thereby regulating such factors as glucose, fat metabolism, skeletal muscle oxygenation and leptin signaling.
If this proved the case, a drug that stimulated the serotonin 5-HT(2c) receptor might decrease the energy efficiency of physical activity, says Tecott. He and his colleagues now are testing this possibility in normal mice.
Notably, serotonin receptors are already the target of numerous drugs that enhance serotonergic transmission, including the appetite suppressant fenfluramine and the depression-treating serotonin reuptake inhibitors. In prior work, Tecott’s team found that the appetite-suppressant effects of fenfluramine were reduced in the 5-HT(2c) receptor mutant mice, implicating the receptor as a target for appetite suppression.
It may be, says Tecott, that in addition to being an appetite suppressor fenfluramine affects energy expenditure. In any case, he says, further studies on the novel physiological process could help explain why some mammals, including mice and humans, tend to get heavier as they get older.
Co-authors of the study were Katsunori Nonogaki PhD, Luna Abdallah, PhD, postdoctoral fellow, Evan H. Goulding, MD, PhD, postdoctoral fellow, and Stephen J. Bonasera, MD, PhD, postdoctoral fellow, all members of the Tecott lab at the time of the studies.
The study was funded by the National Institute of Mental Health, a Howard Hughes Medical Institute Physician Postdoctoral Fellowship and an American Federation for Aging Research Academic Geriatrics Fellowship.