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

Manami Oya; Yoshiki Miyasaka; Yoshiko Nakamura; Miyako Tanaka; Takayoshi Suganami; Tomoji Mashimo; Kazuhiro Nakamura

doi:10.1016/j.cmet.2024.02.010

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

Cell Metab. 2024 Feb 27:S1550-4131(24)00056-1. doi: 10.1016/j.cmet.2024.02.010. Online ahead of print.

Authors

Manami Oya¹, Yoshiki Miyasaka², Yoshiko Nakamura¹, Miyako Tanaka³, Takayoshi Suganami⁴, Tomoji Mashimo⁵, Kazuhiro Nakamura⁶

Affiliations

¹ Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
² Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
³ Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya 464-8601, Japan.
⁴ Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya 464-8601, Japan; Center for One Medicine Innovative Translational Research (COMIT), Nagoya University, Nagoya 464-8601, Japan.
⁵ Institute of Experimental Animal Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Division of Genome Engineering, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁶ Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: kazu@med.nagoya-u.ac.jp.

PMID: 38452767
DOI: 10.1016/j.cmet.2024.02.010

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.

Keywords: aging; brown adipose tissue; cilia; dorsomedial hypothalamus; intraflagellar transport; leptin; melanocortin; obesity; paraventricular hypothalamic nucleus; thermoregulation.