A plastic aggrecan barrier modulated by peripheral energy state gates metabolic signal access to arcuate neurons
Laura Kuczynski-Noyau, Sixtine Karmann, Paolo Alberton, Inés Martínez‐Corral, Sreekala S. Nampoothiri, Florent Sauvé, Tori Lhomme, Carmelo Quarta, Suneel Apte, Sébastien G. Bouret, Attila Aszódi, Sowmyalakshmí Rasika, Philippe Ciofi, Julie Dam, Vincent Prévot, Virginie Mattot
Abstract
The hypothalamic arcuate nucleus (ARH) contains neurons vital for maintaining energy homeostasis that sense and respond to changes in blood-borne metabolic hormones. Despite its juxtaposition to the median eminence (ME), a circumventricular organ lacking a blood-brain barrier and thus exposed to circulating molecules, only a few ventral ARH neurons perceive these extravasating metabolic signals due to a poorly understood ME/ARH diffusion barrier. Here, we show in male mice that aggrecan, a perineural-net proteoglycan deposited by orexigenic ARH neurons, creates a peculiar ventrodorsal diffusion gradient. Fasting enhances aggrecan deposition more dorsally, reinforcing the diffusion barrier, particularly around neurons adjacent to fenestrated capillary loops that enter the ARH. The disruption of aggrecan deposits results in unregulated diffusion of blood-borne molecules into the ARH and impairs food intake. Our findings reveal the molecular nature and plasticity of the ME/ARH diffusion barrier, and indicate its physiological role in hypothalamic metabolic hormone sensing. Energy homeostasis requires brain sensing of peripheral metabolic signals. Here, the authors show that energy-state-dependent aggrecan deposits by hypothalamic neurons at a key interface gate brain entry of blood-borne signals and thus food intake.