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.