6-Shogaol and 6-gingerol, the pungent of ginger, inhibit TNF-alpha mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes.

In this study, we demonstrated that the two ginger-derived components have a potent and unique pharmacological function in 3T3-L1 adipocytes via different mechanisms. Both pretreatment of 6-shogaol (6S) and 6-gingerol (6G) significantly inhibited the tumor necrosis factor-alpha (TNF-alpha) mediated downregulation of the adiponectin expression in 3T3-L1 adipocytes. Our study demonstrate that (1) 6S functions as a PPARgamma agonist with its inhibitory mechanism due to the PPARgamma transactivation, and (2) 6G is not a PPARgamma agonist, but it is an effective inhibitor of TNF-alpha induced c-Jun-NH(2)-terminal kinase signaling activation and thus, its inhibitory mechanism is due to this inhibitory effect.

[1]  R. Kitazawa,et al.  MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. , 2006, The Journal of clinical investigation.

[2]  M. Matsuda,et al.  Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. , 2003, Diabetes.

[3]  K. Sekiya,et al.  Enhancement of insulin sensitivity in adipocytes by ginger , 2004, BioFactors.

[4]  O. Simon,et al.  6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant , 2006, BMC pharmacology.

[5]  K. Miyashita,et al.  Dual action of isoprenols from herbal medicines on both PPARγ and PPARα in 3T3‐L1 adipocytes and HepG2 hepatocytes , 2002 .

[6]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[7]  J. K. Kim,et al.  c-Jun N-terminal kinase is involved in the suppression of adiponectin expression by TNF-α in 3T3-L1 adipocytes , 2005 .

[8]  J. Plutzky,et al.  Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. , 2007, Circulation.

[9]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[10]  T. Suganami,et al.  A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes: Role of Free Fatty Acids and Tumor Necrosis Factor α , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[11]  Xiangdong Wu,et al.  Hydrogen Peroxide Generated during Cellular Insulin Stimulation Is Integral to Activation of the Distal Insulin Signaling Cascade in 3T3-L1 Adipocytes* , 2001, The Journal of Biological Chemistry.

[12]  T. Kadowaki,et al.  Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance* , 2006, Journal of Biological Chemistry.

[13]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[14]  Z. Dong,et al.  Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases* , 2003, Journal of Biological Chemistry.

[15]  L Wood,et al.  Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. , 2001, American journal of physiology. Endocrinology and metabolism.

[16]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[17]  H. Kaneto,et al.  Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide , 2004, Nature Medicine.

[18]  S. Fleming,et al.  A Convenient One-Step Gingerol Synthesis , 1999 .

[19]  T. Saruta,et al.  Adiponectin, an adipocyte-derived protein, predicts future insulin resistance: two-year follow-up study in Japanese population. , 2004, The Journal of clinical endocrinology and metabolism.

[20]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[21]  C. Mobbs,et al.  Adiponectin is stimulated by adrenalectomy in ob/ob mice and is highly correlated with resistin mRNA. , 2002, American journal of physiology. Endocrinology and metabolism.

[22]  Y. Matsuzawa.  Adipocytokines and metabolic syndrome. , 2005, Seminars in vascular medicine.

[23]  D. Seo,et al.  Reversine stimulates adipocyte differentiation and downregulates Akt and p70(s6k) signaling pathways in 3T3-L1 cells. , 2007, Biochemical and biophysical research communications.

[24]  J. Ojewole.  Analgesic, antiinflammatory and hypoglycaemic effects of ethanol extract of Zingiber officinale (roscoe) rhizomes (zingiberaceae) in mice and rats , 2006, Phytotherapy research : PTR.

[25]  S. Yamaoka,et al.  Role of the Toll-like Receptor 4/NF-&kgr;B Pathway in Saturated Fatty Acid–Induced Inflammatory Changes in the Interaction Between Adipocytes and Macrophages , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[26]  J. K. Kundu,et al.  [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-κB in phorbol ester-stimulated mouse skin , 2005, Oncogene.

[27]  Michael Karin,et al.  A central role for JNK in obesity and insulin resistance , 2002, Nature.