Primary Cilia Dysfunction in Brown Fat Results in Fatal Thermogenesis Failure in Neonatal Mice

Primary cilium, microtubule-based sensory organelle that has emerged as a central player in coordinating numerous signaling pathways. Although primary cilia are known to regulate cellular signaling and energy metabolism, the relationship between these roles in the context of ciliopathies and brown adipose tissue (BAT) dysfunction remains poorly understood. To elucidate the role of primary cilia in BAT, we generated Ucp1-Cre;Ift88 ^flox/flox mice with BAT-specific ciliary loss. There were no significant differences in body size, weight, or BAT weight relative to body weight between P0 Ucp1-Cre;Ift88 ^flox/flox and P0 Ucp1-Cre;Ift88 ^+/+ pups. Embryos examined at E14.5 and E18.5 also showed no discernible differences in size, morphology, or histology. However, P0 Ucp1-Cre;Ift88 ^flox/flox pups exhibited neonatal lethality caused by defective thermogenesis, despite preserved Ucp1 expression. These mice displayed markedly reduced ketone body levels in both BAT and serum, accompanied by downregulation of Hmgcs2 , a key enzyme in ketogenesis. Loss of primary cilia in BAT suppressed ketogenesis and increased ROS production through HMGCS2 downregulation, ultimately impairing non-shivering thermogenesis. Remarkably, neonatal lethality of Ucp1-Cre;Ift88 ^flox/flox pups was completely rescued by thermoneutral housing or β-hydroxybutyrate supplementation. Our findings identified a previously unrecognized mechanism by which primary cilia regulate non-shivering, UCP1-independent thermogenesis via ketogenesis.