Growth Hormone Pulses and Liver Gene Expression Are Differentially Regulated by the Circadian Clock Gene Bmal1.

In this study, we found that loss of the circadian clock gene Bmal1 causes disruptions throughout the growth hormone (GH) axis, from hepatic gene expression to production of urinary pheromones and pheromone-dependent behavior. First, we show that Bmal1 knockout (KO) males elicit reduced aggressive responses from wild-type (WT) males and secrete lower levels of major urinary proteins (MUPs); however, we also found that a liver-specific KO of Bmal1 (liver-Bmal1-KO) produces a similar reduction in MUP secretion without a defect in aggressive behavior, indicating that the decrease in elicited aggression arises from another factor. We then shifted our investigation to determine the cause of MUP dysregulation in Bmal1 KO animals. Because the pulse pattern of GH drives sexually dimorphic expression of hepatic genes including MUPs, we examined GH pulsatility. We found that Bmal1 KO males have a female-like pattern of GH release, whereas liver-Bmal1-KO mice are not significantly different from either WT or Bmal1 KO. Since differential patterns of GH release regulate the transcription of many sexually dimorphic genes in the liver, we then examined hepatic gene transcription in Bmal1 KO and liver-Bmal1-KO mice. We found that while some female-predominant genes increase in the Bmal1 KO, there was no decrease in male-predominant genes, and little change in the liver-Bmal1-KO. We also found disrupted serum insulin growth factor 1 (IGF-1) and liver Igf1 messenger RNA in the Bmal1 KO mice, which may underlie the disrupted GH release. Overall, our findings differentiate between GH-pulse-driven and circadian-driven effects on hepatic genes, and the functional consequences of altered GH pulsatility.