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Int. J. Mol. Sci. 2018, 19(10), 3134; https://doi.org/10.3390/ijms19103134 (registering DOI)

Ghrelin Restores the Disruption of the Circadian Clock in Steatotic Liver

1
,
1,* and 1,2,*
1
Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
2
Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346, USA
*
Authors to whom correspondence should be addressed.
Received: 4 July 2018 / Revised: 22 September 2018 / Accepted: 9 October 2018 / Published: 12 October 2018
(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)
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Abstract

Obese mice demonstrate disruption of the circadian clock and feeding cycle. Circulating ghrelin, a hormone secreted mainly by gastric X/Alike cells, is significantly reduced in obese humans and animals. Here, we examined whether ghrelin improves the disruption of the circadian rhythm in steatotic hepatocytes and liver. The effects of ghrelin on hepatic circadian clock genes were studied in steatotic hepatocytes and liver of mice fed a high-fat diet (HFD) for 12 weeks. The circadian clock of cultured hepatocytes was synchronized by treatment with 100 nM dexamethasone for 1 h. Ghrelin was administrated to the cultured hepatocytes (10−8 M) or to mice at a dose of 11 nmol/kg/d for two weeks via a subcutaneous minipump. The mRNA and protein levels of core clock genes were analyzed. Steatosis significantly blunted the circadian pattern of clock genes such as Bmal1, Clock, and Per in cultured hepatocytes and liver. Treatment with ghrelin markedly restored the daily rhythm of the clock genes, with a robust oscillation between peak and trough in cultured hepatocytes isolated from obese mice. It also increased the abundance and expression amplitude of clock genes in steatotic liver, causing the peak of Clock to shift to the dark period and the peak of Per2 to shift to the light period compared with the control groups. Deletion of GHSR1a further deteriorated the derangement of clock gene patterns in obese mice. Ghrelin significantly increased the oscillations of mTOR/S6 signaling. We demonstrate that ghrelin restored the derangement of the circadian rhythm in steatotic liver via mTOR signaling. View Full-Text
Keywords: ghrelin; circadian rhythm; steatotic liver; mTOR; S6 (S6 ribosomal protein) ghrelin; circadian rhythm; steatotic liver; mTOR; S6 (S6 ribosomal protein)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Wang, Q.; Yin, Y.; Zhang, W. Ghrelin Restores the Disruption of the Circadian Clock in Steatotic Liver. Int. J. Mol. Sci. 2018, 19, 3134.

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