A brand new examine means that the explanation why ageing is related to weight problems lies in specific neurons found in the brain [1].
Inform that to the mind
It’s usually exhausting to shed weight, and it turns into tougher with age. Whereas it appears easy sufficient to eat much less, indicators within the mind are telling folks to eat extra. Trendy science is beginning to perceive that it’s, in truth, all within the head, however in a really specific manner.
In a brand new examine revealed in Cell Metabolism, researchers from Nagoya College in Japan investigated an essential participant in anti-obesity signaling within the mind: melanocortin-4 receptor (MC4R). This protein is expressed in a subset of hypothalamic neurons, and genetic deficiencies within the gene that codes for it end in overeating and weight problems in rodents and people [2].
Shorter cilia equal fats
The scientists found that MC4R resides in major cilia, the tiny hairlike protrusions from neuronal our bodies. These are to not be confused with axons, that are a lot greater and longer and are primarily concerned in conducting electrical impulses. Major cilia, which may also be discovered on different cell sorts, are sensory organelles that detect and reply to chemical and mechanical stimuli. In neurons, major cilia regulate varied processes associated to the cells’ improvement and performance. MC4R-positive major cilia had been virtually solely present in two particular hypothalamic areas, DMH and PVH.
The researchers discovered that MC4R in major cilia transfers indicators that enhance vitality expenditure by way of thermogenesis in brown adipose tissue (BAT). Extra importantly, MC4R-positive major cilia appeared to shorten with age, virtually disappearing in outdated overweight rats. Major cilia that didn’t comprise MC4R had been spared from this destiny. MC4R molecules had been evenly distributed alongside cilia size, that means that cilia shortening ends in a proportional decline in MC4R signaling.
Placing rats on a high-fat eating regimen appeared to speed up MC4R-positive cilia shortening, whereas 40% caloric restriction strongly inhibited it. MC4R-positive cilia had been the longest quickly after weaning, when younger rats have the quickest metabolism to assist them generate sufficient warmth. Because the animals develop, their surface-to-mass ratio decreases, together with their vitality calls for per gram of weight; the identical factor occurs to people. Cilia size was negatively correlated with physique fats content material in all animals.
The researchers then knocked down MC4R expression particularly in these two hypothalamic areas by way of RNA interference. This didn’t have cytotoxic results and affected solely MC4R-positive neurons. In consequence, MC4R-positive major cilia had been considerably shortened even in younger rats. This led to each decrease oxygen consumption (indicative of decrease vitality expenditure) and to increased meals consumption. Unsurprisingly, the handled rats had elevated physique weight and fats content material.
The leptin connection
Leptin is a hormone primarily produced by adipose tissue (fats cells) that performs an important function in regulating vitality stability, physique weight, and metabolism. Leptin is upstream from melanocortin, and it helps keep vitality stability by speaking the physique’s vitality standing to the mind. When leptin ranges are excessive, it acts on melanocortin, selling satiety.
Extreme adiposity can set off leptin resistance when leptin ranges are “caught” excessive, making the physique insensitive to the hormone. Leptin resistance, elevated adiposity, and weight achieve are all related to ageing [3]. The researchers needed to understand how the mechanism of cilia shortening that they’d found pertains to leptin resistance. Leptin injections suppressed urge for food in wild-type rats however not in MC4R-deficient rats, suggesting that shortening of MC4R-positive cilia generally is a explanation for leptin resistance.
There may be additionally a silver lining: the researchers discovered that dietary restriction robustly regenerates quick MC4R-positive cilia in aged rats, presumably resulting from lowered leptin-melanocortin signaling. This implies that the age-related predisposition to weight problems is just not everlasting and will be reversed by way of life interventions.
“We consider {that a} related mechanism exists in people as effectively,” stated Professor Kazuhiro Nakamura, the lead creator of the examine. “We hope our discovering will result in a basic therapy for weight problems.” However even earlier than the tablet is developed, in response to Nakamura, “reasonable consuming habits may keep MC4R-positive cilia lengthy sufficient to maintain the mind’s anti-obesity system in good condition whilst we age.”
Literature
[1] Oya, M., Miyasaka, Y., Nakamura, Y., Tanaka, M., Suganami, T., Mashimo, T., & Nakamura, Okay. (2024). Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal major cilia. Cell Metabolism.
[2] Yeo, G. S., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., & O’Rahilly, S. (1998). A frameshift mutation in MC4R related to dominantly inherited human weight problems. Nature genetics, 20(2), 111-112.
[3] Sasaki, T. (2015). Age-associated weight achieve, leptin, and SIRT1: a attainable function for hypothalamic SIRT1 within the prevention of weight achieve and ageing via modulation of leptin sensitivity. Frontiers in endocrinology, 6, 153289.
