Photoperiod Regulates Vitamin A and Wnt/β-Catenin Signaling in F344 Rats

In seasonal mammals, growth, energy balance, and reproductive status are regulated by the neuroendocrine effects of photoperiod. Thyroid hormone (TH) is a key player in this response in a number of species. A neuroendocrine role for the nutritional factor vitamin A has not been considered, although its metabolic product retinoic acid (RA) regulates transcription via the same nuclear receptor family as TH. We hypothesized that vitamin A/RA plays a role in the neuroendocrine hypothalamus alongside TH signaling. Using a reporter assay to measure RA activity, we demonstrate that RA activity levels in the hypothalamus of photoperiod-sensitive F344 rats are reduced in short-day relative to long-day conditions. These lower RA activity levels can be explained by reduced expression of a whole network of RA signaling genes in the ependymal cells around the third ventricle and in the arcuate nucleus of the hypothalamus. These include genes required for uptake (Ttr, Stra6, and Crbp1), synthesis (Raldh1), receptor response (RAR), and ligand clearance (Crapb1 and Cyp26B1). Using melatonin injections into long-day rats, we show that the probable trigger of the fall in RA is melatonin. Surprisingly we also found RPE65 expression in the mammalian hypothalamus for the first time. Similar to RA signaling genes, members of the Wnt/beta-catenin pathway and NMU and its receptor NMUR2 are also under photoperiodic control. Our data provide strong evidence for a novel endocrine axis, involving the nutrient vitamin A regulated by photoperiod and melatonin and suggest a role for several new players in the photoperiodic neuroendocrine response. (Endocrinology 153: 815-824, 2012)