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

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. [Display omitted] • MC4R-bearing primary cilia (MC4R⁺ cilia) of hypothalamic neurons shorten with age • Shortened MC4R⁺ cilia blunt satiety signals, leading to obesity and leptin resistance • Chronic leptin-melanocortin signaling promotes obesogenic shortening of MC4R⁺ cilia • Dietary restriction or Cilk1 knockdown reverses or inhibits MC4R⁺ ciliary shortening The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in the hypothalamus. Oya et al. discovered that MC4R-bearing primary cilia of hypothalamic neurons progressively shorten with age to develop age-related obesity and leptin resistance. This "age-related ciliopathy" is promoted by chronic leptin-melanocortin signaling and inhibited by dietary restriction. [ABSTRACT FROM AUTHOR]