OR22-5 Effect of Melatonin Receptor 1 on Glucose and Lipid Metabolism in Melatonin-proficient (c3hf+ ∕+) Female Mice

Various functions of the pineal gland hormone melatonin are mediated via receptors, MT1 and MT2. Both receptors are known to regulate glucose metabolism in mice and humans. In addition, the MT1 receptor also controls lipid metabolism in mice. Light exposure, jet lag and shift work often cause the inhibition of melatonin production and hence the action of its receptors. So far, the loss of melatonin signaling was studied in male mice only. Here, we analyze the effect of removal of MT1 receptor in female mice under a control diet (CD)/high fat diet (HFD) regimen. Female C3H-f+∕+ (WT) and C3H-f+∕+ MT1 KO (MT1KO) mice (n=9-12/group) at six weeks of age were housed singly and exposed to CD (D12450H, 10% kcal/fat) or HFD (D12451, 45% kcal/fat) for 14 weeks. Weight, food intake and fasting blood glucose level (FBG) of each mouse was measured weekly. Insulin (ITT) and glucose tolerance tests (GTT) were performed after 14 weeks. At the end of experiment, mice were euthanized and liver and blood samples were collected to assess the lipid profile in these samples. RNA-seq was performed on the liver tissue. No difference was seen in weight gain by WT and MT1KO female mice on a CD while MT1KOs tend to gain more weight on HFD than WT mice (16.94g vs 17.26g). WT and MT1KOs consumed same amount of food on CD, but MT1 KOs on HFD ate significantly more food than WT (283.16g vs 323.06g, P<0.05). Under HFD, FBG in MT1KOs was significantly increased with respect to WTs (107.71mg/dL vs 158.50 mg/dL, P<0.05). While no difference in CD mice was seen with IIT and GTT, HFD negatively affected GTT and ITT in MT1 KOs. No difference was observed in the lipid profile (e.g., total cholesterol, triglycerides, phospholipids and free fatty acids) of WT and MT1KO mice under CD, while HFD significantly increased the cholesterol (149.5 vs 225.2 mg/dL, P<0.05) and phospholipids (287.8 vs. 358.6 mg/dL P<0.05) levels in MT1KOs. Finally, HFD leads to a significant increase in lipid deposition in the liver of MT1KOs when compared to other groups (34.46 vs 54.88 mg/g tissue, P<0.05). RNA-seq revealed a higher number (644) of differentially regulated genes and increase in lipid and glucose-related pathways in MT1KO mice with HFD. Our data show that C3H-f+∕+ female mice are protected from diet-induced obesity and its detrimental effects on glucose and lipid metabolism. However, under HFD conditions, removal of MT1 receptor abolishes such a protection. Lack of MT1 also leaded to an increase in lipid deposition in the liver. In conclusion, our data indicate that that melatonin (MT1) signaling is crucial for protection of females from diet induced obesity and its consequences. Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.