Age-Related Changes in Brain Structures Linked to Middle-Age Obesity, Study Finds
A study reveals that middle-age obesity may be caused by the shortening of specific brain structures that regulate metabolism, suggesting that dietary management could be key to prevention.
Researchers in Japan have discovered that obesity in middle age is due to age-related alterations in the form of neurons in the hypothalamus, the brain region responsible for regulating metabolism and appetite.
The Role of Melanocortin-4 Receptor (MC4R)
A protein called melanocortin-4 receptor (MC4R) detects overnutrition and regulates metabolism and appetite to prevent obesity. According to a study conducted on rats, MC4Rs were concentrated in primary cilia (antenna-like structures) that extend from specific groups of hypothalamic neurons. The study also showed that the primary cilia became shorter with age, which decreased MC4Rs accordingly, resulting in weight gain.
“We believe that a similar mechanism exists in humans as well,” said Professor Kazuhiro Nakamura of Nagoya University Graduate School of Medicine, the lead author of the study. “We hope our finding will lead to a fundamental treatment for obesity.” The researchers published the results of the study in the journal Cell Metabolism.
The Mechanism Behind Weight Gain
As individuals age, they become more prone to being overweight and obese, which can lead to various chronic diseases. Previous studies have suggested that middle-aged weight gain is caused by a decline in overall metabolism due to aging, but the specific mechanism was unclear.
A research team from Nagoya University Graduate School of Medicine, in collaboration with researchers from Osaka University, the University of Tokyo, and the Nagoya University Research Institute of Environmental Medicine, conducted a study focusing on MC4Rs.
Shortening of MC4R+ primary cilia in the hypothalamus of the brain leads to middle-age obesity. Credit: Kazuhiro Nakamura
MC4Rs stimulate metabolism and suppress food intake in response to an overeating signal from melanocortin. The research team initially examined the distribution of MC4Rs in the rat brain and found that MC4Rs were present exclusively in primary cilia of specific groups of hypothalamic neurons.
Subsequently, the team investigated the length of the primary cilia that had MC4Rs (MC4R+ cilia) in the brains of young and middle-aged rats. They discovered that MC4R+ cilia in middle-aged rats were significantly shorter than those in young rats. Accordingly, the metabolism and fat-burning capacity of middle-aged rats were much lower than those of their younger counterparts.
Dietary Impact and Leptin Resistance
The research team also analyzed MC4R+ cilia in rats under different dietary conditions. Results showed that MC4R+ cilia in rats on a normal diet gradually shortened with age, while those in rats on a high-fat diet shortened at a faster pace. Conversely, rats on a restricted diet exhibited slower cilia shortening.
Interestingly, the team found that MC4R+ cilia that had disappeared with age were regenerated in rats subjected to two months of dietary restriction.
Through genetic technologies, the team also artificially made MC4R+ cilia shorter in young rats. The study showed that these rats experienced increased food intake and decreased metabolism, leading to weight gain.
Moreover, the team administered a hormone called leptin to the brains of rats with artificially shortened MC4R+ cilia. Although leptin is known to reduce food intake, it surprisingly didn’t reduce appetite in this case, indicating leptin resistance.
“This phenomenon, called leptin resistance, is often observed in obese human patients as well. This is an obstacle to the treatment of obesity, but the cause has long been unknown,” explained Dr. Manami Oya, the first author of the study.
“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 study concluded that the age-related shortening of MC4R+ cilia causes middle-age obesity and leptin resistance in rats and that dietary restriction is one method to prevent and treat overweight and obesity. Professor Nakamura highlighted that moderate eating habits could help maintain MC4R+ cilia long enough to keep the brain’s anti-obesity system in good shape as individuals age.
Reference: “Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia” by Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo and Kazuhiro Nakamura, 6 March 2024, Cell Metabolism. DOI: 10.1016/j.cmet.2024.02.010
