Melatonin signaling protects from the negative effect of light at night on the mouse liver

The hormone melatonin – which regulates many physiological functions within the body - is synthesized at night and its levels are low during the day. Melatonin acts via G protein-coupled receptors named melatonin receptor type 1 (MT1) and type 2 (MT2). These receptors are present in many tissues and activate a wide variety of signaling pathways. Disruption of melatonin synthesis by genetic or environmental factors has been linked to some of the pathologies that have been observed in shift workers. Light at night (LAN) suppresses melatonin levels thus providing a causal link between the effect of LAN on melatonin signaling and health. Indeed, many of the negative effects of LAN in humans are mediated by the MT1 receptor. Our data indicate that in melatonin proficient mice, MT1 signaling is involved in the regulation of glucose metabolism and lipid processing suggesting that melatonin-MT1 signaling in the liver plays an important role in regulating metabolism. The present application comprises two specific aims. In specific aim 1, we will produce liver-specific MT1 knock-out mice in a C57/bl6 melatonin proficient genetic background and then we will test the hypothesis that removal of MT1 signaling only from the liver is responsible for the effects observed in global MT1 KO mice. In specific aim 2 we propose to explore the role of melatonin signaling in the regulation of the liver transcriptomic, and which biological pathways are directly affected by melatonin signaling in the liver and which one may be regulated indirectly by the brain or other tissues. In this proposal, we will develop new lines of transgenic mice in a melatonin-proficient background and our studies will provide new and important insights into the role of melatonin signaling in the liver. Finally, our experiments will provide fundamental data that will allow the development of new pharmacological treatment(s) that may alleviate some of the diseases associated with LAN and shiftwork.