Peripheral and central regulation of thyroid status in teleost fish with particular reference to tetraploid juvenile salmonids and Parr-Smolt transformation

• Thyroid hormone availability to target tissues can be regulated by central or peripheral mechanisms in fish. • Deiodinase enzymes play a primary role in determining peripheral thyroid status in fish. • Deiodinases must act with other TH-regulating pathways to achieve hormone delivery to receptors. • Studies have yet to confirm centrally-driven thyrotropin regulation of thyroid status in fish. • Salmonid whole genome duplication has generated paralogs of thyroid-regulating genes with the potential for novel actions. Mammalian thyroid status is governed by thyroid secretion of L-thyroxine (T 4 ) as a prohormone that is monodeiodinated in peripheral tissues to bioactive T 3 (3,5,3′-triiodo-l-thyronine). T 4 secretion is controlled by the hypothalamic-pituitary-thyroid (HPT) axis (central control) whereas T 3 availability to target cells depends mainly on mechanisms in extrathyroidal tissues such as cellular transport and deiodination (peripheral control). Does this model apply to poikilothermic teleost fish which in contrast to homeothermic mammals may show major surges in plasma T 4 due to season, feeding, reproductive state or stressors? We have evaluated the contributions of central and peripheral mechanisms to fish thyroid status in light of recent discoveries employing both traditional endocrine approaches and more modern molecular biological techniques, focusing primarily on salmonid species which may undergo a unique thyroid-implicated premigratory parr-smolt transition (PST), and which as tetraploids may express multiple paralogs of regulatory peptides. Most teleost research has focused on peripheral control by the three classic deiodinases (D1, D2 and D3). In salmonids they determine systemic (D1, D2) and tissue-specific (D2) T 3 generation from T 4 and the equally critical T 4 and T 3 degradations (D1, D3). Tetraploid salmonids may express up to four paralogs for a given deiodinase, providing the potential for species-specific or tissue-specific T 3 production, curtailment of T 3 action, or iodine recapture. Critical as they appear, salmonid deiodinases do not function in isolation but in concert with, and dependence on, TH plasma transport, cell-membrane translocation, hepatic conjugation, biliary excretion and gastrointestinal metabolism. Two rainbow trout properties are particularly distinct from the mammalian model: i) T 3 , but not T 4 , exchanges rapidly between plasma and erythrocytes permitting plasma T 3 stability despite marked acute changes in plasma T 4 and ii) in contrast to ingested T 4 , which is unavailable from food due to complete gastrointestinal deiodination, ingested T 3 contributes to the plasma T 3 pool. Thus the teleost liver, poised at the confluence of exogenous and endogenous T 3 sources, may play a strategic role through its TH biliary excretion, deiodination and other pathways in regulating systemic T 3 availability involved in anabolic/catabolic balance and somatic growth. A major consequence of ingested T 4 degradation is the exclusive delegation of T 4 availability to the HPT axis. Since mammalian TSH consistently stimulates teleost T 4 secretion a mammal-like HPT central control model has been assumed. However, teleost HPT function differs from that of homeotherms in both its hypothalamic control and response to external stimuli. T 4 secretion could be regulated mainly by T 4 negative feedback with the HPT axis playing a subsidiary role of merely ensuring adequate T 4 substrate for regulated peripheral deiodination to proceed. However, this does not account for the notable surges in salmonid plasma T 4 and implies resetting of the HPT ‘thyrostat’. Thus the role of central TSH control in the regulation of plasma T 4 changes remains unclear, awaiting further characterization of endogenous TSH secretion. Furthermore, discoveries of TSH-subunit and TSH-receptor expression in piscine peripheral tissues such as the CNS, liver, and gonad require reassessment of TSH function with a focus not only on its traditional endocrine actions but also on its potential as a paracrine regulator of TH action in peripheral tissues. In conclusion, while there are many similarities in thyroid regulation between mammals and salmonids there are also key differences. These likely stem from the evolution of homeothermy, the constraints of terrestrial iodine availability and a plasticity in salmonid peripheral and central control resulting from tetraploidy.