Developmental and tissue-specific expression of thyrotropin-releasing hormone signaling genes in zebrafish and its association with glycemic regulation

Thyrotropin-releasing hormone (TRH) is a highly conserved tripeptide classically associated with regulation of the hypothalamic-pituitary-thyroid axis; however, TRH and its receptors are also widely distributed in peripheral metabolic tissues. While TRH has been implicated in glucose homeostasis in mammals, the developmental expression, tissue distribution, and sex-dependent metabolic roles of the TRHergic system in zebrafish remain poorly defined. Here, we characterized the TRHergic system in zebrafish (Danio rerio) by integrating bioinformatic analyses with developmental and adult expression profiling in both sexes, together with functional assessment under hyperglycemic conditions. TRHergic components - including pre proTRH, TRH receptor isoforms, and the TRH-degrading enzyme - were structurally conserved and dynamically expressed during early development, with trh-r1b displaying the most pronounced developmental changes. In adults, these genes exhibited broad central and peripheral expression with marked sex-specific patterns. In vivo, exogenous TRH reduced blood glucose levels in hyperglycemic males but not females. This effect was not associated with a direct insulinotropic response, supporting a modulatory role for TRH in metabolic regulation, likely involving peripheral tissues such as the pancreas and liver. Together, these findings establish zebrafish as a valuable vertebrate model for studying sex-dependent metabolic functions of the TRHergic system, particularly in the context of sex-dependent regulation of glucose homeostasis.