The shape of your brain neurons may change your “shape” in middle age
Researchers in Japan may have cracked the code on middle-age obesity. A new study on rats from Nagoya University finds that changes in neuron shape in the hypothalamus, an area of the brain that regulates appetite and metabolism, could be the key.
A protein known as melanocortin-4 receptor (MC4R) reflects calorie overload and moderates metabolism and appetite to prevent obesity. Based on their study in rats, MC4Rs were found in primary cilia (antenna-like structures) which originate from a couple of groups of hypothalamic neurons. The research also found that the primary cilia shorted with age, which decreased MC4Rs and resulted in weight gain.
Professor Kazuhiro Nakamura of the Nagoya University Graduate School of Medicine and lead author of the study notes, "We believe that a similar mechanism exists in humans as well. We hope our finding will lead to a fundamental treatment for obesity." The study results were published in the journal Cell Metabolism.
As we age, we’re at a higher risk of being overweight and obese. Overweight and obesity raises the risk of diabetes, hyperlipidemia, and other chronic illnesses. Past studies suggest that middle-aged weight gain may be due to a drop in overall metabolism from aging, but the reason wasn’t clear.
A study focusing on MC4Rs was conducted with a research team of the 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.
MC4Rs boost metabolism and reduce food intake in response to an overeating signal from melanocortin. At first, the research team evaluated the distribution of MC4Rs in the rat brain by using an antibody they had created to make MC4Rs visible. They found that MC4Rs are exclusively present in the primary cilia of certain groups of hypothalamic neurons.
The team then examined the length of the primary cilia that had MC4Rs (MC4R+ cilia) in the brains of 9-week-old (young) rats and 6-month-old (middle-aged) rats. The researchers discovered that MC4R+ cilia in middle-aged rats were significantly shorter than those in young rats. As a result, middle-aged rats' metabolism and fat-burning ability were much lower than in young rats.
The researchers then evaluated MC4R+ cilia in rats using different diets. The results indicated that MC4R+ cilia in rats on a normal diet gradually got shorter with age. But MC4R+ cilia in rats on a high-fat diet shortened at a faster rate, while those in rats on a restricted diet shortened at a slower more slowly.
The team also discovered that MC4R+ cilia that initially disappeared with age were recreated in rats with two months of dietary restriction.
Genetic technologies to create MC4R+ cilia shorter in young rats were utilized in the study. These rats had increased food intake and decreased metabolism, resulting in weight gain.
The hormone leptin was also given to the rats with artificially shortened MC4R+ cilia. Leptin may reduce food intake. However, their appetite was not reduced, suggesting leptin could not influence anti-obesity effects.
According to Dr. Manami Oya, the study’s first author, "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,".
"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 indicated that age-related shortening of MC4R+ cilia causes middle-aged obesity and leptin resistance in rats. The researchers showed that dietary restriction is one method to prevent and treat overweight and obesity. Professor Nakamura said, "Moderate eating habits could maintain MC4R+ cilia long enough to keep the brain's anti-obesity system in good shape even as we age."
Here are tips on how your clients can prevent age-related weight gain:
· Get adequate sleep, at least 7 to 8 hours per night. Lack of sleep impacts metabolism and food cravings. 2
· Cut out sugary beverages and high-calorie desserts made with refined carbs. Both are linked with weight gain.
· Obtain adequate protein in your diet to build and maintain muscle mass. 3
· Include strength training exercises twice per week to improve body composition and metabolism.
· Reduce stress to prevent stress eating.
· Follow a calorie-controlled, high-fiber Mediterranean diet. This has been indicated in weight management. 4
· Reduce or avoid alcohol given the risk for metabolic syndrome, weight gain, and fatty liver disease. 5
· Cut out frequent snacking. Pay attention to hunger cues versus habit.
Lisa Andrews, MEd, RD, LD
References:
1. Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo, Kazuhiro Nakamura. Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia. Cell Metabolism, 2024; DOI: 10.1016/j.cmet.2024.02.010
2. The role of insufficient sleep and circadian misalignment in obesity - PubMed (nih.gov)
3. Weight Loss Strategies and the Risk of Skeletal Muscle Mass Loss - PubMed (nih.gov)
4. Mediterranean Diet and Obesity-related Disorders: What is the Evidence? - PubMed (nih.gov)