Middle-age obesity caused by changes in neuron shape

As we get older, we become more prone to being overweight and obesity. Previous studies have suggested that middle-age weight gain is caused by a decline in overall metabolism due to aging, but the mechanism behind this has been unclear. Seeking answers, a research team led by Nagoya University conducted a study in rats, focusing on a protein called melanocortin-4 receptor (MC4R). Their results were published in the journal Cell Metabolism.

MC4Rs stimulate metabolism and suppress food intake in response to an overeating signal from melanocortin, which helps prevent obesity. The research team examined the distribution of MC4Rs in rat brains by utilising an antibody they had developed specifically to make MC4Rs visible. They found that MC4Rs are present exclusively in primary cilia (antenna-like structures) that extend from specific groups of neurons in the hypothalamus — the region of the brain that controls metabolism and appetite.

The team next investigated the length of the primary cilia that had MC4Rs (MC4R⁺ cilia) in the brains of nine-week-old (young) and six-month-old (middle-age) rats. They found that MC4R⁺ cilia in middle-aged rats were significantly shorter than those in young rats. Accordingly, the metabolism and the fat-burning capacity of middle-aged rats were much lower than those of young rats.

The team next analysed MC4R⁺ cilia in rats under different dietary conditions. The results showed that MC4R+ cilia in rats on a normal diet gradually shortened with age. On the other hand, MC4R⁺ cilia in rats on a high-fat diet shortened at a faster pace, while those in rats on a restricted diet shortened at a slower pace. The team also found that MC4R⁺ cilia that once disappeared with age were regenerated in rats raised under two months of dietary restriction.

The team also used genetic technologies to make MC4R⁺ cilia shorter in young rats. These rats showed increased food intake and decreased metabolism, leading to weight gain. In addition, the team administered a hormone called leptin — which is thought to help reduce food intake — to the brains of rats with artificially shortened MC4R⁺ cilia. Surprisingly, however, their appetite was not reduced, indicating that leptin could not exert anti-obesity effects.

“This phenomenon, called leptin resistance, is often observed in obese human patients as well,” said Dr 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.”

The researchers concluded that the age-related shortening of MC4R⁺ cilia causes middle-age obesity and leptin resistance in rats, and they believe a similar mechanism exists in humans as well. They also demonstrated that dietary restriction is one method to prevent and treat overweight and obesity.

“Moderate eating habits could maintain MC4R⁺ cilia long enough to keep the brain’s anti-obesity system in good shape even as we age,” said lead author Professor Kazuhiro Nakamura.

“We hope our finding will lead to a fundamental treatment for obesity.”

Image credit: iStock.com/huettenhoelscher