Long-term and reversible changes in energy balance and growth are characteristic of seasonal animals. These changes are triggered by photoperiod through melatonin and recent work indicates that early events in this response involve altered thyroid hormone and retinoic acid signalling within the ependymal/tanycyte cells of the hypothalamus. In this study we examined signalling downstream of thyroid hormone and retinoic acid, and investigated how this links to the control of energy balance and growth in photoperiod-sensitive F344 rats. Using microarray analysis, we found the most significant changes in genes related to inflammatory pathways and we identified the inflammatory chemokine chemerin (RARRES2) as a candidate physiological effector downstream of retinoic acid regulated transcription in the hypothalamus. Chemerin and its receptor Cmklr1 were expressed in the ependymal cells of the hypothalamus and were higher in long then in short day photoperiod. In hypothalamic slice cultures chemerin signalled through activation of extracellular signal-regulated kinases (ERK) in a time-dependent manner. Acute intracerebroventricular injections of chemerin resulted in a strong decrease in food intake and body weight, accompanied by a dose-dependent change in hypothalamic expression of peptidergic modulators that play a pivotal role in growth and feeding, such as growth-hormone-releasing hormone (GHRH) and pro-opiomelanocortin (POMC). In contrast, chronic infusion of chemerin into the third ventricle of short day housed F344 rats caused a significant increase in food intake together with an increase in POMC mRNA expression thereby mimicking long day conditions. Furthermore, vimentin mRNA was strongly induced after acute chemerin injection, indicating that one of chemerin’s initial actions might be as a driver of cellular and structural re-modelling of the hypothalamus. We conclude that inflammatory signalling downstream of thyroid hormone and retinoic acid is involved in seasonal brain plasticity and reveal a novel pathway within the hypothalamus that contributes to the neuroendocrine control of seasonal physiology.