ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study describes how the primary cilia of hypothalamic neurons bearing melanocortin-4 receptors (MC4R) progressively shorten with age, leading to reduced sensitivity to satiety signals, increased appetite, and obesity. This age-related ciliary shortening is exacerbated by chronic leptin-melanocortin signalling, but can be mitigated by dietary restriction or knockdown of ciliogenesis-associated kinase 1 (CILK1). These findings suggest potential therapeutic approaches to combat obesity and metabolic syndrome in aging populations.

Primary cilia play crucial roles in various signaling pathways, including those involved in metabolic regulation¹. The identification of chronic leptin-melanocortin signaling as a promoter of ciliary shortening highlights a feedback mechanism where prolonged activation of this pathway leads to reduced effectiveness, contributing to obesity. This insight is particularly relevant as it connects hyperleptinemia and leptin resistance, commonly observed in obese individuals, to structural changes in hypothalamic neurons. The reversal or inhibition of ciliary shortening through dietary restriction or CILK1 knockdown indicates that interventions at the molecular level can restore ciliary function and improve metabolic outcomes. This opens avenues for drug development to prevent ciliary shortening, and thereby enhance sensitivity of hypothalamic neurons to satiety signals and promoting energy expenditure. Investigating whether similar mechanisms occur in other types of neurons and tissues could also provide a more comprehensive understanding of aging and obesity.

Reference: 1. DeMars KM, Ross MR, Starr A, McIntyre JC. Neuronal primary cilia integrate peripheral signals with metabolic drives. Front Physiol 2023; 14: 1-14.