| Summary: | Food deprivation in mammals is typically associated with reduced [thyroid hormone] (TH), and deiodinase content and activity to suppress metabolism, but in hibernating, metabolically quiescent ground squirrels, [TH] increase in the presence of reduced TH receptor content and activity making them cryptically hyperthyroid. However, in prolong‐fasted, metabolically active elephant seal pups, TH levels are maintained, if not elevated. The functional relevance of this apparent paradox is unknown and clearly demonstrates variability in the regulation of [TH] and function in food‐deprived mammals. To address the hypothesis that prolonged fasting (7 weeks) increases the expression of deiodinases (DI1/2) and TH receptor (THrβ‐1), we measured the mRNA expression of these genes in adipose and muscle at 1, 3 and 7 wks fasting. Fasting did not decrease plasma [thyroid stimulating hormone] (TSH), total [tri‐iodothyronine] (tT3), free [T3] (fT3), total [thyroxine] ( tT4) and free [T4] (fT4) suggesting that the hypothalamic‐pituitary‐thyroid (HPT) axis is maintained during fasting. The mRNA and protein (except adipose DI1) expressions of adipose and muscle DI1 & 2 increased suggesting that the mechanisms mediating cellular TH activity are increased with prolonged fasting. Fasting also increased adipose and muscle THrβ‐1 mRNA expression. The data demonstrate a unique, atypical mechanism of TH activity and regulation in mammals adapted to prolonged food deprivation in which the potential responsiveness of peripheral tissues and cellular TH activity are increased, likely to meet the energetic demands of prolonged fasting. This unique cellular response may contribute to the seal's adaptation to prolonged fasting, providing insight to therapies for TH‐related pathologies in humans.
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