title: Bilobalide abates inflammation, insulin resistance and secretion of angiogenic factors induced by hypoxia in 3T3-L1 adipocytes by controlling NF-κB and JNK activation.
abstract: Obesity leads to inflammation and insulin resistance in adipose tissue. Hypoxia, observed in obese adipose tissue is suggested as a major cause of inflammation and insulin resistance in obesity. However, the role of hypoxia in adipose tissue during obesity and insulin resistance was not well established. Here we mainly explored the crosstalk between hypoxia induced inflammation, and insulin resistance and also secretion of angiogenic factors in 3T3-L1 adipocytes and possible reversal with bilobalide. Hypoxia for 24h significantly (P≤0.05) increased the secretion of MCP-1 (4.59 fold), leptin (2.96 fold) and reduced adiponectin secretion (2.93 fold). In addition, the mRNA level of resistin (6.8 fold) and TLR4 receptors (8.8 fold) was upregulated in hypoxic adipocytes. The release of inflammatory cytokines and expression of TLR4 receptors led to activation of JNK and NF-κB signalling. We further investigated the effects of JNK and NF-κB activation on insulin signalling receptors. The present study showed increased (P≤0.05) serine 307 phosphorylation of IRS-1 (1.9 fold) and decreased expression of IRS-2 (0.53 fold) in hypoxic group showing hypoxia induced impairment in insulin signalling. Hypoxia significantly (P≤0.05) increased basal glucose uptake (3.3 fold) as well as GLUT-1 expression in adipocytes indicating GLUT-1 mediated glucose uptake. Hypoxia for 24h significantly increased (P≤0.05) the expression of angiogenic factors. Bilobalide protected adipocytes from hypoxia induced inflammation and insulin resistance mainly by reducing inflammatory adipokine secretion, improving adiponectin secretion, reducing NF-κB/JNK activation, and inhibiting serine phosphorylation of IRS-1 receptors of insulin signalling pathway.
authors.affiliation: Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019.
authors.forename: A
authors.initials: A
authors.lastname: Priyanka
authors.affiliation: Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019.
authors.forename: G
authors.initials: G
authors.lastname: Sindhu
authors.affiliation: Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019.
authors.forename: G L
authors.initials: GL
authors.lastname: Shyni
authors.affiliation: Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019.
authors.forename: M R
authors.initials: MR
authors.lastname: Preetha Rani
authors.affiliation: Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019.
authors.forename: V M
authors.initials: VM
authors.lastname: Nisha
authors.affiliation: Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India, 695019. Electronic address: raghukgopal@niist.res.in.
authors.forename: K G
authors.initials: KG
authors.lastname: Raghu
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D046934:Ginkgolides / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009765:Obesity / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D003517:Cyclopentanes; D005663:Furans; D046934:Ginkgolides; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D016328:NF-kappa B; D048670:MAP Kinase Kinase 4; C073710:bilobalide
keywords: 3T3-L1 adipocytes; Bilobalide; Hypoxia; Inflammation; Insulin resistance