Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

M Yamada, Y Saga, N Shibusawa… - Proceedings of the …, 1997 - National Acad Sciences
M Yamada, Y Saga, N Shibusawa, J Hirato, M Murakami, T Iwasaki, K Hashimoto, T Satoh…
Proceedings of the National Academy of Sciences, 1997National Acad Sciences
Thyrotropin-releasing hormone (TRH) is a brain hypothalamic hormone that regulates
thyrotropin (TSH) secretion from the anterior pituitary and is ubiquitously distributed
throughout the brain and other tissues including pancreas. To facilitate studies into the role
of endogenous TRH, we have used homologous recombination to generate mice that lack
TRH. These TRH−/− mice are viable, fertile, and exhibit normal development. However, they
showed obvious hypothyroidism with characteristic elevation of serum TSH level and …
Thyrotropin-releasing hormone (TRH) is a brain hypothalamic hormone that regulates thyrotropin (TSH) secretion from the anterior pituitary and is ubiquitously distributed throughout the brain and other tissues including pancreas. To facilitate studies into the role of endogenous TRH, we have used homologous recombination to generate mice that lack TRH. These TRH−/− mice are viable, fertile, and exhibit normal development. However, they showed obvious hypothyroidism with characteristic elevation of serum TSH level and diminished TSH biological activity. Their anterior pituitaries exhibited an apparent decrease in TSH immunopositive cells that was not due to hypothyroidism. Furthermore, this decrease could be reversed by TRH, but not thyroid hormone replacement, suggesting a direct involvement of TRH in the regulation of thyrotrophs. The TRH−/− mice also exhibited hyperglycemia, which was accompanied by impaired insulin secretion in response to glucose. These findings indicate that TRH−/− mice provide a model of exploiting tertiary hypothyroidism, and that TRH gene abnormalities cause disturbance of insulin secretion resulting in marked hyperglycemia.
National Acad Sciences