Nandinine, a Derivative of Berberine, Inhibits Inflammation and Reduces Insulin Resistance in Adipocytes via Regulation of AMP-Kinase Activity

Abstract

Nandinine is a derivative of berberine that has high efficacy for treating cardiovascular diseases. This study investigated the effects of berberine and nandinine on the regulation of insulin sensitivity in adipocytes. Through treatment with macrophage-derived conditioned medium in 3T3-L1 adipocytes, dysregulation of adipokine production and activation of the IκB kinase β/nuclear factor-kappa B pathway was induced. However, these phenomena were effectively reversed by berberine, nandinine, and salicylate pretreatments. Furthermore, both berberine and nandinine inhibited serine phosphorylation of insulin receptor substrate-1 induced by IκB kinase β and increased tyrosine phosphorylation of insulin receptor substrate-1 to activate the PI3K/Akt pathway, which finally led to insulin-mediated glucose uptake. In addition, berberine and nandinine significantly increased AMP-activated protein kinase activity, thereby contributing to their anti-inflammatory effect by inhibiting IκB kinase β activation. Finally, in vivo studies demonstrated that both berberine (100 or 200 mg/kg) and nandinine (100 or 200 mg/kg) effectively ameliorated glucose intolerance and induced the insulin sensitivity index in mice. In conclusion, berberine and nandinine attenuated insulin resistance in adipocytes by inhibiting inflammation in an AMP-activated protein kinase-dependent manner. Berberine and nandinine may be used as dietary supplements and nandinine is a new candidate for obesity treatment.

Key words

Berberine - nandinine - insulin resistance - 3T3-L1 adipocytes - Inflammation - AMPK

• References

• 1 Heilbronn LK, Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 2008; 14: 1225-1230
• 2 Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415-445
• 3 Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001; 60: 349-356
• 4 Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006; 74: 443-477
• 5 De Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett 2008; 582: 97-105
• 6 Rasouli N, Kern PA. Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 2008; 93: S64-S73
• 7 Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 2007; 100: 328-341
• 8 Yang Z, Kahn BB, Shi H, Xue BZ. Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J Biol Chem 2010; 285: 19051-19059
• 9 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116: 1793-1801
• 10 Piyanuch R, Sukhthankar M, Wandee G, Baek SJ. Berberine, a natural isoquinoline alkaloid, induces NAG-1 and ATF3 expression in human colorectal cancer cells. Cancer Lett 2007; 258: 230-240
• 11 Zhou H, Mineshita S. The effect of berberine chloride on experimental colitis in rats in vivo and in vitro . J Pharmacol Exp Ther 2000; 294: 822-829
• 12 Godugu C, Patel AR, Doddapaneni R, Somagoni J, Singh M. Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid. PLoS One 2014; 9: e89919
• 13 Chen W, Miao YQ, Fan DJ, Yang SS, Lin X, Meng LK, Tang X. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats. AAPS PharmSciTech 2011; 12: 705-711
• 14 Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta 2007; 380: 24-30
• 15 Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85-97
• 16 Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86-100
• 17 Baker RG, Hayden MS, Ghosh S. NF-kappaB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22
• 18 Lee HJ, Joo M, Abdolrasulnia R, Young DG, Choi I, Ware LB, Blackwell TS, Christman BW. Peptidylarginine deiminase 2 suppresses inhibitory {kappa}B kinase activity in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Biol Chem 2010; 285: 39655-39662
• 19 Li J, Houseknecht KL, Stenbit AE, Katz EB, Charron MJ. Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. FASEB J 2000; 14: 1117-1125
• 20 Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med 2004; 10: 65-71
• 21 Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006; 17: 4-12
• 22 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830
• 23 Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev 2012; 249: 218-238
• 24 Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev 2007; 21: 1443-1455
• 25 Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong ZF, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA, Avizonis D, DeBerardinis RJ, Siegel PM, Jones RG. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo . Cell Metab 2013; 17: 113-124
• 26 Salt IP, Palmer TM. Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin Investig Drugs 2012; 21: 1155-1167
• 27 Ou HC, Lee WJ, Wu CM, Chen JF, Sheu WH. Aspirin prevents resistin-induced endothelial dysfunction by modulating AMPK, ROS, and Akt/eNOS signaling. J Vasc Surg 2012; 55: 1104-1115
• 28 Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev 2005; 6: 13-21
• 29 Benomar Y, Gertler A, De Lacy P, Crepin D, Ould Hamouda H, Riffault L, Taouis M. Central resistin overexposure induces insulin resistance through Toll-like receptor 4. Diabetes 2013; 62: 102-114
• 30 Herschkovitz A, Liu YF, Ilan E, Ronen D, Boura-Halfon S, Zick Y. Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance. J Biol Chem 2007; 282: 18018-18027
• 31 Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 2012; 11: 230-241
• 32 Abel ED, OʼShea KM, Ramasamy R. Insulin resistance: metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol 2012; 32: 2068-2076
• 33 Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab 2009; 296: E955-E964
• 34 Wilcox G. Insulin and insulin resistance. Clin Biochem Rev 2005; 26: 19-39
• 35 Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP, Gattinoni L. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 2013; 123: 4479-4488
• 36 Salama RM, Schaalan MF, Elkoussi AA, Khalifa AE. Potential utility of sodium selenate as an adjunct to metformin in treating type II diabetes mellitus in rats: a perspective on protein tyrosine phosphatase. Biomed Res Int 2013; 2013: 231378