title: Vitamin D supplementation inhibits oxidative stress and upregulate SIRT1/AMPK/GLUT4 cascade in high glucose-treated 3T3L1 adipocytes and in adipose tissue of high fat diet-fed diabetic mice.
abstract: This study examined the hypothesis that vitamin-D prevents oxidative stress and upregulates glucose metabolism via activating insulin-independent signaling molecules in 3T3-L1 adipocytes and in high fat diet (HFD)-fed mice. To investigate the mechanism 3T3L1 adipocytes were treated with high glucose (HG, 25 mM) and 1,25(OH)2D3(1,25-dihydroxyvitamin D3) (0-50 nM). Results showed that 1,25(OH)2D3supplementation decreased NOX4 expression, ROS production, NF-κB phosphorylation, and increased the expression of Nrf2 and Trx in HG-treated cells. 1,25(OH)2D3supplementation upregulated SIRT1 expression and AMPK phosphorylation and stimulated the IRS1/PI3K/PIP3/AKT/PKCζ signaling cascade, GLUT4 expression, and glucose uptake in HG-treated adipocytes. The effect of 1,25(OH)2D3on the phosphorylation of both AMPK and IRS1, GLUT4 expression, and glucose uptake was significantly inhibited in SIRT1-knockdown adipocytes. This suggests the role of insulin-independent signaling molecules (SIRT1, AMPK) in mediating the effect of 1,25(OH)2D3on the signaling cascade of glucose uptake. In addition, cholecalciferol supplementation significantly upregulated pAMPK, SIRT-1 and GLUT-4 levels in adipose tissue of mice fed with HFD. This study demonstrates a novel molecular mechanism by which vitamin-D can prevent oxidative stress and upregulates glucose uptake via SIRT1/AMPK/IRS1/GLUT4 cascade in HG-treated adipocytes and in adipose tissue of HFD diabetic mice.
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, 71103, United States.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Manna
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, 71103, United States.
authors.forename: Arunkumar E
authors.initials: AE
authors.lastname: Achari
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, 71103, United States. Electronic address: sjain@lsuhsc.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat; D019587:Dietary Supplements; D005347:Fibroblasts / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D015854:Up-Regulation; D014807:Vitamin D / Q000737:chemistry*
chemical_list: D051275:Glucose Transporter Type 4; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018167:Receptors, Calcitriol; C495693:Slc2a4 protein, mouse; D014807:Vitamin D; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Glucose metabolism; High glucose; Oxidative stress; SIRT1/AMPK/IRS1/GLUT4; Vitamin D