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A mechanism of middle-aged obesity
Manami Oya (Kazuhiro Nakamura)

We gain weight more easily as we age. Although previous studies suggest that middle-aged obesity is caused by an age-related decline in metabolism, the mechanism has not been elucidated. In this study, we focused on the melanocortin-4 receptor (MC4R), whose activation by leptin–melanocortin satiety signaling in the hypothalamus leads to increased metabolism and decreased appetite to avoid obesity.
To investigate age-related changes in the molecular dynamics of the MC4R in the hypothalamus, we developed a specific antibody against the MC4R protein and used it to study the localization of MC4Rs in the rat brain. We found that MC4Rs localize to neuronal primary cilia, an antenna-like structure, in two specific regions of the hypothalamus. Surprisingly, MC4R-bearing (MC4R+) primary cilia were found to gradually shorten with age, accelerated by a high-fat diet and suppressed by dietary restriction.
Next, MC4R+ primary cilia in young rats were forced to shorten using a genetic technique. This manipulation caused a decrease in metabolism and an increase in appetite, leading to an increase in body fat percentage and body weight. In addition, these rats exhibited leptin resistance, a condition in which the satiety signaling molecule leptin can exert only blunted appetite inhibition, as observed in many obese patients.
Based on these results, we propose a mechanism of middle-aged obesity, in which age-related shortening of MC4R+ primary cilia, which is promoted by overnutrition, reduces sensitivity to satiety signals in the hypothalamus, leading to decreased metabolism and increased food intake to develop obesity.

Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo, and Kazuhiro Nakamura
Age-related ciliopathy: obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia
Cell Metabolism 36(5): 1044-1058, 2024.

<Figure Legends>
(Top) MC4R+ primary cilia in the dorsomedial hypothalamus (DMH) and paraventricular hypothalamic nucleus (PVH) gradually shortened with age.
(Bottom) A proposed mechanism of middle-aged obesity. Age-related shortening of MC4R+ primary cilia, which is accelerated by overnutrition, impairs sensitivity to satiety signals, thereby decreasing metabolism, increasing food intake, and ultimately developing middle-aged obesity and leptin resistance.

Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan