A new role for the hypothalamus to control body vitamin A homeostasis

Vitamin A is an essential lipid-soluble dietary micronutrient and is under tight homeostatic regulation control at a 1 μM concentration. It is stored as retinyl esters in the liver, released in the circulation primarily as retinol while retinoic acid (RA) the active metabolite regulates gene transcription. The hypothalamus is the key integrative region of the brain for the regulation of neuroendocrine system and body homeostasis. But how vitamin A homeostasis is controlled is unknown. We hypothesised that homeostatic regulation of plasma retinol involves sensing of retinol by hypothalamic tanycytes, cells that line the third ventricle. To investigate this, rats were grouped randomly and 5 μL of 10 μΜ RA, retinol or DMSO (vehicle) was stereotactically injected into the third ventricle of a rat brain. In a separate study, retinoids in the mouse hypothalamus were altered through retinol-binding protein 4 (Rbp4) gene knockdown. Six and twenty-four hours post injection, samples were obtained for retinol and retinyl quantification, mRNA transcripts and proteins expression involved in homeostasis. Retinol and RA injection in the rat hypothalamus induced significant changes in genes and proteins in the liver regulating retinol homeostasis. Similarly, quantification of retinol and its ester showed a significant change in stored retinyl palmitate in the liver, liver retinol and circulatory serum retinol. Also, prolonged disruption of Rbp4 in the region of the arcuate nucleus of the mouse hypothalamus altered retinol levels in the liver. This supports the concept that the brain may sense retinoids and influence whole-body vitamin A homeostasis with a possible ‘‘vitaminostatic’’ role.