Melatonin receptor 1 signaling modulates the metabolic response to high-fat diet in female melatonin-proficient mice

Melatonin plays an important role in the regulation of several physiological functions, including the regulation of circadian rhythms, sleep and reproduction. Recent studies have also reported melatonin signaling via its G-protein coupled receptors (namely MT1 and MT2), affects glucose metabolism, insulin sensitivity, and blood lipid levels. However, most of these studies have been conducted with melatonin-deficient male mice. In the present study, we investigated the effects of a low-fat diet (LFD) and high-fat diet (HFD) on liver biology and transcriptome using melatonin-proficient female mice (C3H-f+/+) and MT1 knockout mice. Our results demonstrate that MT1 deletion alone does not cause notable changes in weight, lipid profile or hepatic lipid accumulation, whereas the combination of MT1 deficiency and HFD exposure results in significant changes in glucose tolerance, serum lipid profiles and lipid accumulation in the liver. In addition, removal of MT1 signaling also induced significant changes in the liver transcriptome that were exacerbated by exposure to HFD. Finally, our data indicate that MT1 deletion was associated with changes in estrogen-related hepatic transcriptional pathways and circulating estradiol levels. These results suggest that MT1 signaling contributes to the metabolic and hepatic response to HFD in female mice. Our study also suggests that these effects may be associated with changes in estrogen-related signaling observed in MT1 KO mice under HFD conditions, although further studies are required to determine causality.