Hypothalamic Thyroid Hormone Catabolism Acts as a Gatekeeper for the Seasonal Control of Body Weight and Reproduction

Abstract

Seasonal adaptations in physiology exhibited by many animals involve an interface between biological timing and specific neuroendocrine systems, but the molecular basis of this interface is unknown. In this study of Siberian hamsters, we show that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions. The expression of the gene encoding type III deiodinase (Dio3) and Dio3 activity in vivo (catabolism of T(4) and T(3)) is dynamically and temporally regulated by photoperiod, consistent with the loss of hypothalamic T(3) concentrations under short photoperiods. Chronic replacement of T(3) in the hypothalamus of male hamsters exposed to short photoperiods, thus bypassing synthetic or catabolic deiodinase enzymes located in cells of the ependyma of the third ventricle, prevented the onset of short-day physiology: hamsters maintained a long-day body weight phenotype and failed to undergo testicular and epididymal regression. However, pelage moult to a winter coat was not affected. Type II deiodinase gene expression was not regulated by photoperiod in these hamsters. Collectively, these data point to a pivotal role for hypothalamic DIO3 and T(3) catabolism in seasonal cycles of body weight and reproduction in mammals.

Maternal photoperiod programs hypothalamic thyroid status via the fetal pituitary gland

“…Although in the present study we focused primarily on the reproductive axis, seasonal changes in hypothalamic T3 availability are also linked to body mass change and the capacity to express torpor (15,21). Independent of seasonal studies, the ependymal zone in which dio2/dio3-expressing tanycytes reside is a recognized hypothalamic stem cell niche, implicated in maintenance of normal metabolic regulation (22).…”

“…Through this conserved pathway, lengthening photoperiod increases the expression of dio2 relative to dio3, producing an euthyroid state in the basal hypothalamus and leading to expression of a spring/summer-like endocrine physiology (e.g., increased body mass and reproductive activation in rodents). Declining photoperiod is associated with the opposite effect (e.g., decrease in body mass, reproductive arrest, and hibernation in rodents) through a relative increase in dio3 expression (15,16).…”

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…TH controls growth‐associated physiology but T3, the most active TH metabolite, does not directly regulate genes involved in this process and gene targets of TH in the hypothalamus have proved enigmatic (Barrett et al, 2007). This study shows that, in vivo , T3 very rapidly induces expression of a key enzyme, Raldh1 , required for RA synthesis by tanycytes, the source of RA for the hypothalamus (Shearer et al, 2010).…”

“…Hyperthyroid rats show an upregulation of the orexigenic gene agouti‐related protein ( Agrp ) in the hypothalamus accompanied by a decrease in proopiomelanocortin ( Pomc ), the precursor of the anorexigen alpha‐melanocyte‐stimulating hormone (α‐MSH; Varela et al, 2012). In addition, the importance of TH signalling in the hypothalamus is highlighted in the regulation of energy balance of seasonal animals (Barrett et al, 2007). This highly conserved pathway is now considered to be the basis of long‐term changes in energy balance, growth and reproduction, in birds and mammals.…”

“…In Siberian hamsters, hypothalamic implants releasing T3 promote long day‐like (i.e. summer‐like) reproductive and body weight responses (Murphy et al, 2012) and conversely local delivery of T3 is able to block short day (winter‐like)‐induced weight loss (Barrett et al, 2007). From these findings it is now generally concluded that local hypothalamic T3 availability is responsible for long‐term seasonal changes in energy metabolism.…”