Disruption of Melatonin Signaling Leads to Lipids Accumulation in the Liver of Melatonin Proficient Mice

Melatonin signaling via melatonin receptor type 1 (MT₁) and type 2 (MT₂) plays an important role in the regulation of several physiological functions. Studies in rodents and humans have demonstrated that disruption of melatonin signaling may affect glucose metabolism, insulin sensitivity, and leptin levels. Accumulating experimental evidence also indicates that in rodents the administration of exogenous melatonin has a beneficial effect on the blood lipid levels. However, the molecular mechanism by which melatonin signaling may regulate lipids is still unclear. In addition, most of the studies with mice have been performed in melatonin-deficient mice by administering exogenous melatonin at supraphysiological doses. Hence the results of these studies may be greatly affected by these two factors. In this study, we report the effects of melatonin signaling removal on the liver biology and transcriptome using melatonin-proficient mice (C3H-f^+/f+) in which MT₁ or MT₂ have been genetically ablated. Our data indicate that the absence of MT₁ or MT₂ signaling leads to disruption of the blood lipids profile and an increase in lipids deposition in the liver. These effects were more pronounced in the mice lacking MT₁ than MT₂. The gene expression profiles obtained with RNA-seq from the livers of the three genotypes revealed that removal of MT₁ affected the transcription of 4255 genes (i.e., 40.6%). Conversely, the removal of MT₂ affected the transcription of 1864 transcripts (i.e., 17.2%). Finally, we identified a group of 13 genes involved in lipids biology that may play a key role in the accumulation of lipids in the liver when melatonin signaling is disrupted. In conclusion, our study indicates that melatonin signaling is an important modulator of liver physiology and metabolism. Our study also indicated that the removal of MT₁ signaling is more deleterious than MT₂ removal.