日本名古屋大学Kazuhiro Nakamura课题组发现，黑色素皮质素-4受体（MC4R）神经元的初级纤毛会发生肥胖性缩短。相关论文于2024年3月6日发表于国际学术期刊《细胞-代谢》杂志。

研究人员发现大鼠下丘脑神经元中含有MC4R的初级纤毛会随着年龄的增长而逐渐变短，这与年龄依赖性代谢下降和脂肪增加有关。这种"与年龄相关的纤毛病"是由营养过剩诱发的瘦素-黑色素信号转导上调产生，而饮食限制或敲除纤毛生成相关激酶1（CILK1）可抑制或逆转这种纤毛病。

通过基因编辑缩短下丘脑神经元中带有MC4R的纤毛，会损害神经元对黑色皮质素的敏感性，导致棕色脂肪产热和能量消耗减少，食欲增加，最终导致肥胖和瘦素抵抗。因此，尽管瘦素具有急性抗肥胖作用，但长期的瘦素-黑色素皮质素信号传导会促进与年龄相关的MC4R纤毛缩短，从而增加肥胖的发生率。这项研究揭示了与年龄相关肥胖症的机制，并且肥胖会增加代谢综合征的风险。

据悉，通常肥胖与衰老有关。然而，尚不清楚年龄相关肥胖症的机理。在下丘脑中黑色素皮质素-4受体介导瘦素-黑色素皮质素抗肥胖信号的传导。

附：英文原文

Title: Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia

Author: Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo, Kazuhiro Nakamura

Issue&Volume: 2024-03-06

Abstract: Obesity is often associated with aging. However, the mechanism of age-related obesity is unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in the hypothalamus. Here, we discovered that MC4R-bearing primary cilia of hypothalamic neurons progressively shorten with age in rats, correlating with age-dependent metabolic decline and increased adiposity. This “age-related ciliopathy” is promoted by overnutrition-induced upregulation of leptin-melanocortin signaling and inhibited or reversed by dietary restriction or the knockdown of ciliogenesis-associated kinase 1 (CILK1). Forced shortening of MC4R-bearing cilia in hypothalamic neurons by genetic approaches impaired neuronal sensitivity to melanocortin and resulted in decreased brown fat thermogenesis and energy expenditure and increased appetite, finally developing obesity and leptin resistance. Therefore, despite its acute anti-obesity effect, chronic leptin-melanocortin signaling increases susceptibility to obesity by promoting the age-related shortening of MC4R-bearing cilia. This study provides a crucial mechanism for age-related obesity, which increases the risk of metabolic syndrome.

DOI: 10.1016/j.cmet.2024.02.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00056-1