Circadian modulation of hepatic transcriptome in transgenic rats expressing human growth hormone

Abstract

The secretory profile of growth hormone (GH) is sexually dimorphic in rats. In male transgenic (TG) rats expressing human GH (hGH) that we generated, the circulating levels of both hGH and endogenous GH are flattened with no male-type pulsatility. To elucidate the regulatory role of episodic GH profile on the liver, the hepatic transcriptome of male TG rats at the middle of the light and dark phases was characterized by genome-wide analyses as compared with that of male wild-type (WT) rats. Transcripts commonly up- or down-regulated regardless of the lighting conditions in TG rats were mainly enriched in the metabolism of xenobiotics. In TG rats, the gene expression profile was functionally feminized, verifying that the sexually dimorphic profile of GH rather than genetic sexuality is a stronger sex-determining factor on the hepatic transcriptome. The common transcripts which fluctuated during the day in both TG and WT rats were enriched in circadian rhythm signaling, and physiological rhythmicity was considered to be finely interconnected with liver metabolism via sexually dimorphic GH secretion. In contrast, some genes were differentially regulated in TG rats at only one of two time points measured, and others were fluctuated daily in only one genotype. In particular, some genes involved in the GH signaling pathway were included, suggesting the signal transduction is circadian-modulated depending upon the GH profile. Our transcriptome analyses clarified the regulatory role of episodic GH profile on the liver and strengthen the functional link between sexually dimorphic GH secretion, liver metabolism, and its circadian regulation.