A Nagoya University study reveals that midlife obesity can be caused by shortening of certain brain structures that regulate metabolism, suggesting that dietary management may be the key to prevention. ing.
Researchers from Nagoya University and Japan have found that obesity in middle age is due to age-related changes in the morphology of neurons in the hypothalamus, a brain region responsible for regulating metabolism and appetite. .
A protein called melanocortin 4 receptor (MC4R) detects overnutrition and regulates metabolism and appetite to prevent obesity. Studies in rats showed that MC4R was concentrated in primary cilia (antenna-like structures) that extend from several groups of hypothalamic neurons. This study also showed that primary cilia become shorter with age, and MC4R decreases accordingly, resulting in weight gain.
“A similar mechanism is thought to exist in humans,” says Professor Kazuhiro Nakamura of the same graduate school. Nagoya University School of Medicine, lead author of the study. “We hope that our findings will lead to fundamental treatments for obesity.” The researchers published their findings in the journal cell metabolism.
Mechanism of weight gain
As we age, we are more likely to become overweight and obese. Obese people are more susceptible to diabetes, hyperlipidemia, and other chronic diseases. Previous research has suggested that the cause of middle-aged weight gain is an overall decline in metabolism due to aging, but the mechanism was unclear.
A research team from the Nagoya University Graduate School of Medicine conducted a study focused on MC4R in collaboration with researchers from Osaka University, the University of Tokyo, and the Nagoya University Institute of Environmental Medicine.
Shortening of MC4R+ primary cilia in the hypothalamus of the brain leads to obesity in middle age.Credit: Kazuhiro Nakamura
MC4R stimulates metabolism and suppresses food intake in response to overeating signals from melanocortins. The research team initially investigated the distribution of MC4R in rat brains using an antibody they developed specifically to visualize MC4R. They found that MC4R is present only in the primary cilia of a specific group of hypothalamic neurons.
The team next investigated the length of primary cilia bearing MC4R (MC4R+ Cilia) are present in the brains of 9-week-old (young) and 6-month-old (middle-aged) rats. The team discovered MC4R.+ The cilia of middle-aged rats were significantly shorter than those of young rats. Therefore, the metabolism and fat burning capacity of middle-aged rats was much lower than that of young rats.
Effects of diet and leptin resistance
The team then analyzed MC4R+ Rat cilia under different dietary conditions.The result is that MC4R+ The cilia of rats fed a normal diet gradually become shorter with age.On the other hand, MC4R+ The cilia of rats fed a high-fat diet shortened at a faster rate, while those of rats fed a restricted diet shortened at a slower pace.
Interestingly, the team also discovered MC4R.+ In rats kept under food restriction for two months, the cilia that had once disappeared with age regenerated.
In the study, the team also used genetic technology to create MC4R.+ Young rats have shorter cilia. These rats showed increased food intake and decreased metabolism, leading to weight gain.
The researchers also administered a hormone called leptin to the brains of rats with artificially shortened MC4Rs.+ Cilia. Leptin is thought to help reduce food intake. However, surprisingly, their appetite did not decrease, indicating that leptin was unable to exert any anti-obesity effects.
“This phenomenon, called leptin resistance, is also commonly observed in obese human patients. It has been an obstacle to obesity treatment, but its causes have long been unknown,” said Manami Oya, lead author of the study. The doctor explained.
“In obese patients, adipose tissue secretes excess leptin, which causes the chronic effects of melanocortin. Our study shows that this may promote age-related shortening of the MC4R. suggests+ It destroys cilia and sends the animal into a downward spiral, rendering melanocortin ineffective and increasing the risk of obesity. ”
This study concluded that age-related shortening of MC4R was responsible.+ Cilia cause midlife obesity and leptin resistance in rats. Researchers have demonstrated that dietary restriction is one way to prevent and treat overweight and obesity. Professor Nakamura said, “A moderate diet can maintain MC4R.”+ Cilia are long enough to keep the brain’s anti-obesity system in good condition as we age. ”
Reference: “Age-related ciliopathies: Obesogenic shortening of primary cilia of melanocortin 4 receptor-bearing neurons” Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Yuji Mashita, Kazuhiro Nakamura, 2024. March 6th, cell metabolism.
DOI: 10.1016/j.cmet.2024.02.010
