A research group from Nagoya University, Osaka University, and the University of Tokyo has discovered that the cause of age-related obesity (so-called middle-aged weight gain), in which people tend to gain weight as they age, is due to age-related regression of the primary cilia of hypothalamic neurons. They found that this is due to a decrease in melanocortin type 4 receptor (MC4R).
Declining whole body metabolism with aging is thought to be one of the causes of age-related obesity, but the mechanism is not clear. This research group focused on MC4R, which has anti-obesity functions. When the hormone leptin, which is secreted from white adipocytes when fat accumulates, acts on the hypothalamus, melanocortin, a satiety signal molecule, is secreted. When MC4R receives melanocortin, it promotes metabolism and suppresses feeding, playing an important role in preventing obesity. Therefore, we investigated how the localization of MC4R changes with age in rats.
As a result, they discovered that MC4R is localized in the antenna structure of the primary cilia of hypothalamic neurons, and that the primary cilia gradually retract (shorten) with age. We also found that the regression of MC4R-localized primary cilia was accelerated under overnutrition conditions and suppressed under food intake restriction.
To investigate the effects of MC4R-localized primary cilia retraction, we found that when we artificially regressed MC4R-localized primary cilia in young rats using genetic technology, their metabolism decreased, food intake increased, and they became fat. Conversely, inhibiting the regression of MC4R-localized primary cilia suppressed obesity.
Based on this, it is thought that when primary cilia regress due to aging or overnutrition (satiation) and MC4R decreases, sensitivity to melanocortin (satiation signal) decreases, leading to obesity. It has been shown that the length of MC4R-localized primary cilia determines the ease with which one can lose weight, and this finding is expected to lead to the development of pharmaceuticals that prevent the regression of primary cilia. By approaching the root cause of obesity, this research result is a breakthrough that will lead to the development of preventive methods and new treatments for various lifestyle-related diseases caused by obesity at the pre-symptomatic stage.
Paper information:【Cell Metabolism】Age-related ciliopathy: obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia
