A change in shape to a particular structure of neurons was found to have a significant impact on obesity in rats. Researchers believe the finding will translate to humans and could help us fight our own middle-aged bulges one day.
Researchers from Nagoya University, Osaka University and other institutions in Japan undertook the rodent study to try to see how the shape of neurons and the way they change with age might be related to obesity. They focused on a protein called melanocortin-4 (MC4R), which is a chemical messenger in the brain that works to suppress food intake when the body senses too much caloric input.
They found that MC4R accumulates in the antennae-like structures known as primary cilia in several groups of neurons in the hypothalamus region of the brain. The MC4R in these structures is activated by an overeating signal delivered by hormones known as melanocortins.
Armed with that information, the scientists set out to see if cilia structure changed in young versus older mice and if so, if that could account for the reason why the pounds tend to pack on as we age. Sure enough, the MC4R cilia were quite a bit shorter in middle-aged rats (aged six months) than in their younger brethren (aged nine weeks). This corresponded to a more sluggish metabolism and fat-burning ability in the older rodents.
"We believe that a similar mechanism exists in humans as well," said Kazuhiro Nakamura of the Nagoya University Graduate School of Medicine, the lead author of the study. "We hope our finding will lead to a fundamental treatment for obesity."
Taking a closer look at MC4R, the researchers put one group of rats on a standard diet to establish a baseline of cilia shrinkage with age. Then they put two other groups on either a high-fat diet or a restricted diet. They found that the rats enjoying the high-fat meals saw their MC4R cilia shrink faster with age, while those on the restricted diets had slower-shrinking cilia (try saying that five times fast).
Looking at the situation from yet a different perspective, the team also genetically engineered shortened MC4R cilia in young rats. This led the rodents to eat more, have reduced metabolisms, and gain weight, thus reinforcing the link between short MC4R cilia and obesity.
Finally the researchers examined the way in which a hormone known as leptin functioned in the experimental rats. Leptin is a hormone that is believed to help regulate appetite. Sensitivity to Leptin has been examined in relation to obesity in many studies, including one that targeted an enzyme in fat cells that could alter their sensitivity to the hormone and lead to rapid weight loss. In this study, rats with shortened cilia given leptin saw no appetite-reduction effects.
"This phenomenon, called leptin resistance, is often observed in obese human patients as well" said Manami Oya, the first author of the study. "This is an obstacle to the treatment of obesity, but the cause has long been unknown.
"In obese patients, adipose tissue secretes excessive leptin, which triggers the chronic action of melanocortin. Our study suggests that this may promote the age-related shortening of MC4R+ cilia and put animals into a downward spiral where melanocortin becomes ineffective, increasing the risk of obesity."
Of course, more studies will be needed to see if the findings translate to human subjects. For now, Nakamura echoes the not-very-fun weight-loss advice specialists have been saying for decades: watch what you eat.
"Moderate eating habits could maintain MC4R cilia long enough to keep the brain’s anti-obesity system in good shape even as we age," he said.
The study has been published in the journal Cell Metabolism.
Source: Nagoya University via EurekAlert
