Increased sensitivity of thyroid hormone-mediated signaling despite prolonged fasting

Abstract

Thyroid hormones (TH) can increase cellular metabolism. Food deprivation in mammals is typically associated with reduced thyroid gland responsiveness, in an effort to suppress cellular metabolism and abate starvation. However, in prolonged-fasted, elephant seal pups, cellular TH-mediated proteins are up-regulated and TH levels are maintained with fasting duration. The function and contribution of the thyroid gland to this apparent paradox is unknown and physiologically perplexing. Here we show that the thyroid gland remains responsive during prolonged food deprivation, and that its function and production of TH increase with fasting duration in elephant seals. We discovered that our modeled plasma TH data in response to exogenous thyroid stimulating hormone predicted cellular signaling, which was corroborated independently by the enzyme expression data. The data suggest that the regulation and function of the thyroid gland in the northern elephant seal is atypical for a fasted animal, and can be better described as, “adaptive fasting”. Furthermore, the modeling data help substantiate the in vivo responses measured, providing unique insight on hormone clearance, production rates, and thyroid gland responsiveness. Because these unique endocrine responses occur simultaneously with a nearly strict reliance on the oxidation of lipid, these findings provide an intriguing model to better understand the TH-mediated reliance on lipid metabolism that is not otherwise present in morbidly obese humans. When coupled with cellular, tissue-specific responses, these data provide a more integrated assessment of thyroidal status that can be extrapolated for many fasting/food deprived mammals.

Adipose transcriptome analysis provides novel insights into molecular regulation of prolonged fasting in northern elephant seal pups

“…Downregulation of these genes is consistent with known metabolic adjustments in fasting seals. While thyroid signaling and sensitivity increase during fasting in elephant seals (38), the TH transporter SLC16A2 is downregulated during fasting in mice (50), similar to what we observed in fasting NES pups. SLC16A2 downregulation in this study suggests that modulation of tissue-specific TH sensitivity is likely to be complex in fasting seals and warrants further investigation.…”

“…Blubber was collected from two separate groups of weaned pups, one group sampled 1-2 wk postweaning ("early," n ϭ 6), and the other group sampled 6 -8 wk postweaning ("late," n ϭ 6). Plasma hormone levels and expression of target genes and proteins in blubber of the same animals have been previously published (38,39).…”

“…Fasting seals exhibit chronically elevated triglycerides, insulin resistance, and increased thyroid hormone receptor availability, deiodinase activity, and expression of TH-mediated target genes and proteins coupled with increases in lipid metabolism and fatty acid mobilization (37-39, 41, 42, 61-64). In addition, the expression of lipid metabolic regulator genes such as peroxisome proliferator-activated receptor gamma coactivator-1␣ (PGC-1␣) and uncoupling protein 2 (UCP2) is upregulated over the duration of fasting in parallel with the upregulation of TH signaling, providing an intriguing insight into natural TH-mediated reliance on lipid metabolism in seals that is not present in morbidly obese humans with similar levels of adiposity (37)(38)(39).…”

Microarray and metabolome analysis of hepatic response to fasting and subsequent refeeding in zebrafish (Danio rerio)

“…This adaptation to starvation was also found in other species [21]. Fasting is usually characterized by decreased cellular metabolism and reduced thyroid hormone (TH) concentration in plasma [7, 22], but the regulation of the TH system in peripheral tissues appears to be complicated. The triiodothyronine (T3) content was significantly increased with reduced type I deiodinase (DIO1) and increased type 3 deiodinase (DIO3) in mice livers after 28 and 36 h of fasting [23].…”

“…The triiodothyronine (T3) content was significantly increased with reduced type I deiodinase (DIO1) and increased type 3 deiodinase (DIO3) in mice livers after 28 and 36 h of fasting [23]. In prolonged fasted northern elephant seal pups, the mRNA levels of dio1 , dio2 and thyroid hormone receptor b ( thrb ) were increased in muscle and adipose [24], which was called “adaptive fasting” by the authors [22]. According to our microarray results, the mRNA expression of thrb and dio2 were increased in the liver after 3 weeks of fasting, while dio1 expression was decreased.…”