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Articles
  • OpenAccess
  • 2,4-Dinitrophenol Downregulates Genes for Diabetes and Fatty Liver in Obese Mice  [ICDM 2015]
  • DOI: 10.4236/jbm.2015.39007   PP.44 - 51
  • Author(s)
  • Qian Gao, Jiang He, Tao Liao, Qingping Zeng
  • ABSTRACT
  • Whether obesity is a disease or a risk factor of metabolic diseases including type 2 diabetes and fatty liver remains debating, we report here that a high-fat diet (HFD) alone or HFD-combined intramuscular injection with a high dose (1.2 mg/kg) of lipopolysaccharide (LPS) induces mouse peripheral noninflammatory obesity. In contrast, HFD-combined intraperitoneal injection with a low dose (0.25 mg/kg) of LPS induces mouse visceral low-grade inflammatory obesity. While the noninsulin-dependent diabetes mellitus (NIDDM) and nonalcoholic fatty liver disease (NAFLD)- related genes are globally upregulated in HFD + low-dose LPS mice, NIDDM and NAFLD genes are not extensively upregulated in HFD + high-dose LPS mice. The mitochondrial uncoupler 2,4-dini- trophenol (DNP) in the dosage of 16 mg/kg was found to exert a weight-reducing effect in obese mice by compromising NF-κB-primed inflammatory responses, thereby down regulating NIDDM and NAFLD genes. Conclusively, mouse visceral low-grade inflammatory obesity that predisposes NIDDM and NAFLD can be ameliorated by DNP via anti-inflammation.

  • KEYWORDS
  • Obesity, Metabolic Disease, Low-Grade Inflammation, 2,4-Dinitrophenol, Anti-Inflammation
  • References
  • [1]
    Lee, Y.S., Kim, J.W., Osborne, O., Ohda, Y., Sasik, R., et al. (2014) Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity. Cell, 157, 1339-1352.
    http://dx.doi.org/10.1016/j.cell.2014.05.012
    [2]
    Jais, A., Einwallner, E., Sharif, O., Gossens, K., Lu, T.T., et al. (2014) Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man. Cell, 158, 25-40.
    http://dx.doi.org/10.1016/j.cell.2014.04.043
    [3]
    Heinrichsdorff, J. and Olefsky, J.M. (2012) Fetuin-A: The Missing Link in Lipid-Induced Inflammation. Nature Medicine, 18, 1182-1183.
    http://dx.doi.org/10.1038/nm.2869
    [4]
    Ding, S., Chi, M.M., Scull, B.P., Rigby, R., Schwerbrock, N.M., et al. (2010) High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates with Obesity and Insulin Resistance in Mouse. PLoS One, 5, e12191.
    http://dx.doi.org/10.1371/journal.pone.0012191
    [5]
    Kim, K.A., Gu, W., Lee, I.A., Joh, E.H. and Kim, D.H. (2012) High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway. PLoS One, 7, e47713.
    http://dx.doi.org/10.1371/journal.pone.0047713
    [6]
    Asterholm, I.W., Tao, C., Morley, T.S., Wang, Q.A., Delga-do-Lopez, F., et al. (2014) Adipocyte Inflammation Is Essential for Healthy Adipose Tissue Expansion and Remodeling. Cell Metabolism, 20, 103-118.
    http://dx.doi.org/10.1016/j.cmet.2014.05.005
    [7]
    Zhao, L., Zhong, S., Qu, H., Xie, Y., Cao, Z., et al. (2015) Chronic Inflammation Aggravates Metabolic Disorders of Hepatic Fatty Acids in High-Fat Diet-Induced Obese Mice. Scientific Reports, 5, 10222.
    http://dx.doi.org/10.1038/srep10222
    [8]
    Perry, R.J., Zhang, D., Zhang, X.M., Boyer, J.L. and Shulman, G.I. (2015) Controlled-Release Mitochondrial Protonophore Reverses Diabetes and Steatohepatitis in Rats. Science, 347, 1253-1256.
    http://dx.doi.org/10.1126/science.aaa0672
    [9]
    Hiernaux, J.R., Baker, P.J., Delisi, C. and Rudbach, J.A. (1982) Mod-ulation of the Immune Response to Lipopolysaccharide. Journal of Immunology, 128, 1054-1058.
    [10]
    Wells, M.T., Gaffin, S.L., Wessels, B.C., Brock-Utne, J.G., Jordaan, J.P., et al. (1990) Anti-LPS Antibodies Reduce Endotoxemia in Whole Body 60Co Irradiated Primates: A Preliminary Report. Aviation Space and Environmental Medicine, 61, 802-806.
    [11]
    Kelly, D., Delday, M.I. and Mulder, I. (2012) Microbes and Microbial Effector Moleculesin Treatment of Inflammatory Disorders. Immunological Reviews, 245, 27-44.
    http://dx.doi.org/10.1111/j.1600-065X.2011.01079.x
    [12]
    Bao, F., Wu, P., Xiao, N., Qiu, F. and Zeng, Q.-P. (2012) Nitric Oxide-Driven Hypoxia Initiates Synovial Angiogenesis, Hyperplasia and Inflammatory Lesions in Mice. PLoS ONE, 7, e34494.
    http://dx.doi.org/10.1371/journal.pone.0034494
    [13]
    Imajo, K., Fujita, K., Yoneda, M., Nozaki, Y., Ogawa, Y., et al. (2012) Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatis Is Regulated by Leptin-Mediated Signaling. Cell Metabolism, 16, 44- 54.
    http://dx.doi.org/10.1016/j.cmet.2012.05.012
    [14]
    Petersen, A.M. and Pedersen, B.K. (2005) The Anti-Inflammatory Effect of Exercise. Journal of Applied Physiology, 98, 1154-1162.
    http://dx.doi.org/10.1152/japplphysiol.00164.2004
    [15]
    Baker, R.G., Hayden, M.S. and Ghosh, S. (2011) NF-κB, Inflammation, and Metabolic Disease. Cell Metabolism, 13, 11-22.
    http://dx.doi.org/10.1016/j.cmet.2010.12.008
    [16]
    Clancy, R.M., Gomez, P.F. and Abramson, S.B. (2004) Nitric Oxide Sustains Nuclear Factor Kappa B Activation in Cytokine-Stimulated Chondrocytes. Osteoarthritis Cartilage, 12, 552-558.
    http://dx.doi.org/10.1016/j.joca.2004.04.003
    [17]
    Wang, D.T., He, J., Wu, M., Li, S.M., Gao, Q., et al. (2015) Artemi-sinin Mimics Calorie Restriction to Trigger Mitochondrial Biogenesis and Compromisetelomere Shortening in Mice. Peer Journal, 3, e822.
    [18]
    Pelletier, A. and Coderre, L. (2007) Ketone Bodies Alter Dinitrophenol-Induced Glucose Uptake through AMPK Inhibition and Oxidative Stress Generation in Adult Cardiomyocytes. American Journal of Physiologicaland Endocrinological Metabolism, 292, E1325-E1332.
    http://dx.doi.org/10.1152/ajpendo.00186.2006
    [19]
    Hawley, S.A., Fullerton, M.D., Ross, F.A., Schertzer, J.D., Chevt-zoff, C., et al. (2012) The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase. Science, 336, 918-922.
    http://dx.doi.org/10.1126/science.1215327
    [20]
    Ford, R.J., Fullerton, M.D., Pinkosky, S.L., Day, E.A., Scott, J.W., et al. (2015) Metformin and Salicylate Synergistically Activate Liver AMPK, Inhibit Lipogenesis and Improve Insulin Sensitivity. Biochemical Journal, 468, 125-132.
    http://dx.doi.org/10.1042/BJ20150125
    [21]
    Kapeller, R., Toker, A., Cantley, L.C. and Carpenter, C.L. (1995) Phos-phoinositide 3-Kinase Binds Constitutively to Alpha/Beta-Tubulin and Binds to Gamma-Tubulin in Response to Insulin. Journal of Biological Chemistry, 270, 25985-25991.
    http://dx.doi.org/10.1074/jbc.270.43.25985
    [22]
    Tsuchiya, K., Sakai, H., Suzuki, N., Iwashima, F., Yoshimoto, T., et al. (2007) Chronic Blockade of Nitric Oxide Synthesis Reduces Adiposity and Improves Insulin Resistance in High Fat-Induced Obese Mice. Endocrinology, 148, 4548-4556.
    http://dx.doi.org/10.1210/en.2006-1371
    [23]
    Shimizu, I., Aprahamian, T., Kikuchi, R., Shimizu, A., Papanicolaou, K.N., et al. (2014) Vascular Rarefaction Mediates Whitening of Brown Fat in Obesity. Journal of Clinical Investigation, 124, 2099-2112.
    http://dx.doi.org/10.1172/JCI71643

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