期刊
JOURNAL OF PINEAL RESEARCH
卷 64, 期 3, 页码 -出版社
WILEY
DOI: 10.1111/jpi.12462
关键词
Circadian; insulin sensitivity; liver; melatonin receptor 1; metabolism; PI3K
资金
- National Institute of General Medical Sciences [2GM116760]
- National Heart and Lung Institute [HL103104]
- National Institute of Diabetes and Digestive and Kidney Diseases [093000]
- National Institute of Neurological Disorders and Stroke [5U54NS083932]
- National Eye Institute [EY022216, EY026291]
- National Institute of Minority Health [RR03034]
- National Institutes of Health [SC2GM116760, S21MD000101, G12-RR03034, U54RR026137, U2C-DK093000]
- NATIONAL CENTER FOR RESEARCH RESOURCES [G12RR003034, U54RR026137] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R01EY022216, R01EY026291] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL103104] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U2CDK093000] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [SC2GM116760] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U54NS083932] Funding Source: NIH RePORTER
- National Institute on Minority Health and Health Disparities [S21MD000101] Funding Source: NIH RePORTER
Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) in the pathogenesis of type 2 diabetes. Here, we report that mice lacking MT1 (MT1 KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT1 was the activation of phosphatidylinositol-3-kinase (PI3K). Transcripts of both catalytic and regulatory subunits of PI3K were strongly downregulated within MT1 KO mice. Moreover, the suppression of nocturnal melatonin levels within WT mice, by exposing mice to constant light, resulted in impaired PI3K activity and insulin resistance during the day, similar to what was observed in MT1 KO mice. Inversely, administration of melatonin to WT mice exposed to constant light was sufficient and necessary to restore insulin-mediated PI3K activity and insulin sensitivity. Hence, our data demonstrate that the activation of MT1 signaling at night modulates insulin sensitivity during the day via the regulation of the PI3K transcription and activity. Lastly, we provide evidence that decreased expression of MTNR1A (MT1) in the liver of diabetic individuals is associated with poorly controlled diabetes.
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