Endocrinology and Metabolism

Original Articles

Diabetes, obesity and metabolism
Protective Effects of Melatonin in High-Fat Diet-Induced Hepatic Steatosis via Decreased Intestinal Lipid Absorption and Hepatic Cholesterol Synthesis: Hyungjune Ku, Yeonji Kim, Alvin Lyle Kim, Garam Lee, Youngsik Choi, Bukyung Kim; Endocrinol Metab. 2023;38(5):557-567. Published online September 1, 2023; DOI: https://doi.org/10.3803/EnM.2023.1672

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Background
The preventative effect of melatonin on the development of obesity and the progression of fatty liver under a high-fat diet (HFD) has been well elucidated through previous studies. We investigated the mechanism behind this effect regarding cholesterol biosynthesis and regulation of cholesterol levels.
Methods
Mice were divided into three groups: normal chow diet (NCD); HFD; and HFD and melatonin administration group (HFD+M). We assessed the serum lipid profile, mRNA expression levels of proteins involved in cholesterol synthesis and reabsorption in the liver and nutrient transporters in the intestines, and cytokine levels. Additionally, an in vitro experiment using HepG2 cells was performed.
Results
Expression of hepatic sterol regulatory element-binding protein 2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and low-density lipoprotein receptor (LDLR) demonstrated that melatonin administration significantly reduces hepatic cholesterol synthesis in mice fed an HFD. Expression of intestinal sodium-glucose transporter 1 (SGLT1), glucose transporter 2 (GLUT2), GLUT5, and Niemann-pick C1-like 1 (NPC1L1) demonstrated that melatonin administration significantly reduces intestinal carbohydrate and lipid absorption in mice fed an HFD. There were no differences in local and circulatory inflammatory cytokine levels among the NCD, HFD, and HFD+M group. HepG2 cells stimulated with palmitate showed reduced levels of SREBP, LDLR, and HMGCR indicating these results are due to the direct mechanistic effect of melatonin on hepatocytes.
Conclusion
Collectively, these data indicate the mechanism behind the protective effects of melatonin from weight gain and liver steatosis under HFD is through a reduction in intestinal caloric absorption and hepatic cholesterol synthesis highlighting its potential in the treatment of obesity and fatty liver disease.

Citations

Citations to this article as recorded by

Influence of dark deprivation on the ultrastructure and mitochondrial apparatus of rat hepatocytes
D Areshidze
Morphology.2024;[Epub] CrossRef

Diabetes, Obesity and Metabolism
Inhibition of miR-146a-5p and miR-8114 in Insulin-Secreting Cells Contributes to the Protection of Melatonin against Stearic Acid-Induced Cellular Senescence by Targeting Mafa: Shenghan Su, Qingrui Zhao, Lingfeng Dan, Yuqing Lin, Xuebei Li, Yunjin Zhang, Chunxiao Yang, Yimeng Dong, Xiaohan Li, Romano Regazzi, Changhao Sun, Xia Chu, Huimin Lu; Endocrinol Metab. 2022;37(6):901-917. Published online December 7, 2022; DOI: https://doi.org/10.3803/EnM.2022.1565

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Abstract PDF Supplementary Material PubReader ePub

Background
Chronic exposure to elevated levels of saturated fatty acids results in pancreatic β-cell senescence. However, targets and effective agents for preventing stearic acid-induced β-cell senescence are still lacking. Although melatonin administration can protect β-cells against lipotoxicity through anti-senescence processes, the precise underlying mechanisms still need to be explored. Therefore, we investigated the anti-senescence effect of melatonin on stearic acid-treated mouse β-cells and elucidated the possible role of microRNAs in this process.
Methods
β-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated β-galactosidase staining. Gain- and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked β-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to predict the direct targets of microRNAs.
Results
Long-term exposure to a high concentration of stearic acid-induced senescence and upregulated miR-146a-5p and miR- 8114 expression in both mouse islets and β-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced β-cell senescence and dysfunction was observed after silencing miR-146a-5p and miR-8114. Moreover, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) was verified as a direct target of miR-146a-5p and miR-8114. Melatonin also significantly ameliorated senescence and dysfunction in miR-146a-5pand miR-8114-transfected β-cells.
Conclusion
These data demonstrate that melatonin protects against stearic acid-induced β-cell senescence by inhibiting miR-146a- 5p and miR-8114 and upregulating Mafa expression. This not only provides novel targets for preventing stearic acid-induced β-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.

Citations

Citations to this article as recorded by

Genome-wide analysis in PC6 electroacupuncture to ameliorate carfilzomib-induced cardiotoxicity in mice
Yuxuan Chen, Rou Peng, Yi Qian, Yizhou Lu, Liyao Chen, Meiling Yu, Minjiao Jiang, Wei Wu, Shengfeng Lu
Gene.2024; 897: 148090. CrossRef
MiR-126 and miR-146a as Melatonin-Responsive Biomarkers for Neonatal Brain Ischemia
Maria Cristina Albertini, Tania Vanzolini, Serafina Perrone, Michael D. Weiss, Giuseppe Buonocore, Valentina Dell’Orto, Walter Balduini, Silvia Carloni
Journal of Molecular Neuroscience.2023; 73(9-10): 763. CrossRef

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