| Title: | Growth Hormone Pulses and Liver Gene Expression Are Differentially Regulated by the Circadian Clock Gene Bmal1 |
| Author(s): | Schoeller EL; Tonsfeldt KJ; Sinkovich M; Shi R; Mellon PL; |
| Address: | "Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California, USA" |
| ISSN/ISBN: | 1945-7170 (Electronic) 0013-7227 (Print) 0013-7227 (Linking) |
| Abstract: | "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" |
| Keywords: | "ARNTL Transcription Factors/genetics/*metabolism Aggression Animals Behavior, Animal *Circadian Rhythm Female *Gene Expression Growth Hormone/*genetics/metabolism Liver/*metabolism Male Mice Mice, Knockout Proteins/genetics/metabolism Sex Characteristics;" |
| Notes: | "MedlineSchoeller, Erica L Tonsfeldt, Karen J Sinkovich, McKenna Shi, Rujing Mellon, Pamela L eng R01 HD100580/HD/NICHD NIH HHS/ T32 HD007203/HD/NICHD NIH HHS/ P42 ES010337/ES/NIEHS NIH HHS/ P30 DK063491/DK/NIDDK NIH HHS/ P30 CA023100/CA/NCI NIH HHS/ R01 DK044838/DK/NIDDK NIH HHS/ F32 HD090837/HD/NICHD NIH HHS/ R01 HD072754/HD/NICHD NIH HHS/ R01 HD082567/HD/NICHD NIH HHS/ T32 DK007044/DK/NIDDK NIH HHS/ P50 HD028934/HD/NICHD NIH HHS/ T32 DK007541/DK/NIDDK NIH HHS/ P50 HD012303/HD/NICHD NIH HHS/ R24 HD102061/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural 2021/02/05 Endocrinology. 2021 Apr 1; 162(4):bqab023. doi: 10.1210/endocr/bqab023" |
