Obesity in Middle Age is Caused by Changes in the Shape of Neurons in the Brain

Obesity is a widespread problem in the western world. Many factors play a role in this. Recent research has discovered a mechanism in the brains of rats that is responsible for obesity in middle age. The experts believe that a similar mechanism also exists in humans. This discovery could lead to improvements in the prevention of obesity and metabolic syndrome.

Age-Related Shortening of MC4R+ Cilia in the Brain Increases the Risk of Obesity

Researchers at Nagoya University and their colleagues in Japan have found that obesity in middle age is caused by age-related changes in the shape of neurons in the hypothalamus, a region of the brain that controls metabolism and appetite. A protein called melanocortin-4 receptor (MC4R) recognizes overeating and regulates metabolism and appetite to prevent obesity. According to their study in rats, the MC4Rs were concentrated in primary cilia (antenna-like structures) that emanate from some groups of hypothalamic neurons. The study also showed that primary cilia became shorter with age, resulting in a corresponding decrease in MC4Rs, which led to weight gain. The researchers believe that a similar mechanism exists in humans and hope that their discovery will lead to a fundamental treatment for obesity. The researchers published the results of the study in the journal Cell Metabolism.

MC4Rs stimulate metabolism and suppress food intake in response to a melanocortin signal that signals overeating. First, the research team investigated the distribution of MC4Rs in the rat brain using an antibody they had specially developed to visualize MC4Rs. They found that MC4Rs are found exclusively in the primary cilia of certain groups of hypothalamic neurons. Next, the team examined the length of primary cilia containing MC4Rs (MC4R+ cilia) in the brains of 9-week-old (young) rats and 6-month-old (middle-aged) rats. The team found that MC4R+ cilia in middle-aged rats were significantly shorter than those of young rats. Accordingly, the metabolism and fat-burning capacity of middle-aged rats were significantly lower than those of young rats.

Next, the team analyzed MC4R+ cilia in rats under different dietary conditions. The results showed that MC4R+ cilia gradually shortened with age in rats on a normal diet. On the other hand, MC4R+ cilia shortened faster in rats fed a high-fat diet, while cilia shortened more slowly in rats on a restricted diet. Interestingly, the team also found that MC4R+ cilia that once disappeared with age were regenerated in rats reared under a two-month diet restriction.

Restricted Diet to Prevent and Treat Overweight and Obesity

In the study, the team also used genetic technologies to shorten MC4R+ cilia in young rats. These rats showed increased food intake and decreased metabolism, which led to weight gain. The team also administered a hormone called leptin to the brains of rats with artificially shortened MC4R+ cilia. Leptin is thought to help reduce food intake. Surprisingly, however, their appetite was not reduced, suggesting that leptin had no anti-obesity effect. This phenomenon, known as leptin resistance, is also frequently observed in obese people. This is an obstacle to the treatment of obesity, but the cause was unknown for a long time. In obese patients, the adipose tissue secretes excessive amounts of leptin, which triggers the chronic effect of melanocortin. The study suggests that this could promote the age-related shortening of MC4R+ cilia and put the animals in a downward spiral in which melanocortin becomes ineffective, increasing the risk of obesity.

The study concluded that age-related shortening of MC4R+ cilia leads to obesity and leptin resistance in middle-aged rats. The researchers demonstrated that dietary restriction is a 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 in old age.