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

Abstract

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/β-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.

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…Further evidence for the involvement of vitamin A and RA in growth and energy balance comes from the study of photoperiodic animals such as hamsters which display increased growth and feeding under long day (summer‐like) conditions compared to short (winter‐like) daylength. Many components of the RA signalling pathway are upregulated in the hypothalamus of long day‐acclimatized rodents including the retinoic X receptor (RXR) which can heterodimerize with either the TH receptor or the RA related receptor (Helfer et al, 2012; Ross et al, 2005; Ross et al, 2004; Shearer et al, 2010; Shearer et al, 2012b). Finally, the importance of Raldh1 in energy balance is highlighted in the finding that Raldh1 −/− mice are highly resistant to diet‐induced obesity (Ziouzenkova et al, 2007).…”

“…This phenotype was ascribed to an excess of retinaldehyde in adipose tissue due to a lack of Raldh1. However, more recent studies have identified Raldh1 as the only RA‐synthesizing enzyme in the mouse hypothalamus (Helfer et al, 2012; Shearer et al, 2010) and therefore the downregulation of hypothalamic RA signalling in Raldh1 −/− mice may also play a role in prevention of obesity.…”

Untitled

“…Another study provides 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. Melatonin is known to mediate the physiological effects of short-day photoperiod in mammals 55,56 .…”

Molecular basis for regulating seasonal reproduction in vertebrates

“…In the photoresponsive rat strain Fischer 344, the retinoic acid (RA) signaling pathway is also activated in LD conditions (Helfer et al 2012, Tavolaro et al 2015.…”