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

Abstract

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.Thyrotropin-releasing hormone (TRH) was originally isolated as the first hypothalamic hormone (1, 2) and has been shown to be present in many organs, including the central nervous system, reproductive system, and gastrointestinal tract (3, 4). Administration of exogenous TRH to animals and humans has been observed to cause a variety of endocrine and nonendocrine biological activities (3-5). The results of these studies have led to the suggestion that TRH may act as a neurotransmitter or neuromodulator in many organs.Because of the ubiquitous distribution of TRH in many organs and the lack of a suitable method to produce selective changes in in vivo TRH level, it has been difficult to examine the mechanism by which TRH regulates different biological activities. For example, TRH is the major regulator of synthesis and secretion of thyrotropin (TSH) in the anterior pituitary and, thus, it plays a pivotal role in the regulation of the hypothalamic-pituitary-thyroid axis. However, the contribution of TRH in the functional maturation of pituitary thyrotrophs during development remains obscure. Second, although isolated deficiency of TRH has been suggested to be the cause of tertiary (hypothalamic) hypothyroidism, there is neither direct clinical evidence nor an animal model to support this hypothesis. In the pancreas, TRH exists in the islets of Langerhans and more specifically within the ␤ cells producing insulin (6-9). However, due to technical difficulties associated with selective depletion of TRH in the ␤ cells, it has been difficult to discern its role in insulin physiology.In view of the aforementioned observations, it is clear that the availability of a TRH-deficient animal model will greatly enhance our ability to clarify the precise role of the peptide in many organ functions.We recently cloned and characterized a mouse hypothalamic cDNA and genomic DNA...

Dynamic expression of Thyrotropin‐releasing hormone in the mouse definitive endoderm

“…The absence of the main target of TRH, TSH, from the early mouse embryo strongly suggests that TRH is acting in a novel manner, perhaps through TRHR2. The precise function of TRH in the early embryo is difficult to determine as there are no obvious definitive endoderm formation or patterning defects in TRH-deficient mice (Yamada et al, 1997(Yamada et al, , 2003. However, the effect of loss of TRHR2 in mice has yet to be determined.…”

“…During mouse embryogenesis, Trh mRNA has been detected in the neural folds at E8.0, at the midbrain-hindbrain junction from E8.5 to E10.5, and in the developing hypothalamus from E11.5 to E18.5 (Schonemann et al, 1995;Michaud et al, 1998Michaud et al, , 2000Acampora et al, 1999;Wang and Lufkin, 2000;Keith et al, 2001;Backman et al, 2003;Goshu et al, 2004;Caqueret et al, 2006;Jukkola et al, 2006). Despite the critical role of TRH in regulating the HPT axis and its expression in developing neural structures, mice deficient in Trh are viable and fertile (Yamada et al, 1997(Yamada et al, , 2003.…”

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

“…The hypothalamic tri-peptide, thyrotrophin-releasing hormone (TRH), is essential for the normal biosynthesis and release of thyroid stimulating hormone (TSH) from the anterior pituitary and in turn, thyroid hormones from the thyroid gland [65]. Although TRH neurons are located in a number of hypothalamic nuclei [38], the hypophysiotrophic TRH neurons which project to the median eminence to regulate anterior pituitary TSH release are confined to the medial and periventricular parvocellular regions of the PVN [29].…”

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

“…Due to the noteworthy instability of pGlu-TRH in the circulation (halflife below 10 min) (23), a direct determination in plasma is not feasible. However, the HPT axis hormones TSH and T4 are the major mediators of TRH in the periphery, and therefore the concentration of the other axis hormones is used to mirror the effect of TRH in vivo (24,25). The depletion of QC resulted in a statistically significant decrease of the serum T4 concentration in male QC ϩ/Ϫ and QC Ϫ/Ϫ mice by 20 and 24%, respectively ( Fig.…”

“…For a comparison with our QC knock-out line pbd-02, TRH knock-out mice (25) showed a doubling of serum TSH, accompanied by a 50% reduction of the serum T4 and significantly impaired glucose tolerance. Notably, tests of oral glucose tolerance and insulin secretion of QC Ϫ/Ϫ mice did not reveal any impairment, supporting a very restricted effect on the HPT axis (Fig.…”