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Objectives: The hypothalamic-pituitary-thyroid (HPT) axis plays a significant role in the regulation of energy expenditure. Previous reports demonstrated that thyroid hormones are critically involved in metabolic process, and hypothyroidism was induced by fasting. The mechanism by which TRH neurons sense alterations in peripheral energy stores is supposed to be regulated by leptin, an adipose tissue-derived hormone. Leptin was initially considered as a hormone to prevent obesity, it was later showed that the major role of leptin is to signal the switch from the fed to the starved state at the hypothalamic level. Recently, we generated TRH-deficient mice (TRH-/-). The mice exhibit tertiary/central hypothyroidism with characteristic elevation of serum TSH level and diminished TSH biological activity. In this study, we used TRH-/- to investigate the physiological role of TRH in fasting energy expenditure, including the mechanism regulated by leptin. Methods: Twelve-week-old male F2 hybrid ICR mice were used in this study. (1) Wild-type mice (WT) and TRH-/- were fasted up to 50 hrs. Blood samples were collected from tail veins at various points. Anterior pituitary samples were obtained from euthanized mice before and after 16 hrs fasting. (2) Serum free T4 (FT4) and TSH levels assessed. (3) The expression level of TSHβ mRNA in anterior pituitary were detected using qPCR assays. (4) We repeated these experiments using mice with leptin administration; leptin (0.5μg/g•BW) was administrated every 6 hours starting at after 2 hours fasting. Results: In WT, the level of FT4 was decreased chronologically during fasting to approximately 50% at 50 hrs after fasting. Serum TSH decreased to 70% and the expression level of TSHβ mRNA in anterior pituitary also decreased to 30% compared to before fasting. Administration of leptin recovered the level of FT4 to basal level. However, the level of serum TSH and TSHβ mRNA in pituitary were not recovered to basal levels. By contrast, in TRH-/-, the level of FT4 were also decreased after fasting indicating that the decrease of FT4 by fasting was independent of TRH. However, the level of FT4 was not recovered by leptin suggesting that the recovery of FT4 by leptin was TRH dependent. Serum TSH level decreased to 75% after fasting, and no recovery to basal level with leptin administration was observed in TRH-/- same as WT. In TRH-/-, the pituitary TSHβ mRNA expression level was about 50% of WT before fasting. It did not correlate with the serum TSH level. In addition, no increase in TSHβ mRNA expression level by leptin administration was observed in TRH-/-. These findings suggested that the TSHβ mRNA expression level in the pituitary is completely TRH-dependent in TRH-/-. Conclusion: Fasting-induced hypothyroxinemia was independent of TRH. Leptin regulates H-P-T axis via TRH during fasting-induced energy expenditure. Leptin may modulate the biological activity of TSHβ.

Leptin Regulates Hypothalamus-Pituitary-Thyroid Axis via TRH in Energy Expenditure During Fasting: The Study on TRH Deficient Mouse