Endocrine Pharmacology

Downregulation of STEAP4, a highly-expressed TNF-α-inducible gene in adipose tissue, is associated with obesity in humans

Article metrics



To determine the relationship between six-transmembrane epithelial antigen of the prostate 4 (STEAP4) expression and obesity.


RT–PCR and immunoblot analyses were performed to determine the differential expressions of STEAP4 mRNA and protein, respectively, in human omental adipose tissue from obese patients and normal weight controls. The expression pattern of STEAP4 mRNA in various human tissues was determined by RT–PCR. The subcellular localization of the STEAP4 protein in human adipose tissue was confirmed by immunohistochemistry. Finally, we confirmed that cultured human omental adipose tissue undergoes TNF-α-mediated regulation of the STEAP4 expression.


STEAP4 mRNA and protein levels were downregulated in omental adipose tissue from obese patients relative to normal controls. The STEAP4 expression was most abundant in human adipose tissue. An immunohistochemical analysis confirmed that STEAP4 was associated with the plasma membrane of adipocytes. The STEAP4 expression was induced by TNF-α in a dose-dependent manner in human adipose tissue.


STEAP4 was abundantly expressed in human adipose tissue, and the STEAP4 expression was significantly downregulated in obese patients. STEAP4 localized to the plasma membrane of adipocytes, and the STEAP4 expression was induced by TNF-α in adipose tissue. These data suggest that STEAP4 may play a significant role in the development of human obesity.


  1. 1

    Spiegelman BM, Flier JS . Obesity and the regulation of energy balance. Cell 2001; 104: 531–43.

  2. 2

    Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–81.

  3. 3

    Visscher TL, Seidell JC . The public health impact of obesity. Annu Rev Public Health 2001; 22: 355–75.

  4. 4

    Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, et al. Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci USA 1996; 93: 6025–30.

  5. 5

    Diatchenko L, Lukyanov S, Lau YF, Siebert PD . Suppression subtractive hybridization: a versatile method for identifying differentially expressed genes. Methods Enzymol 1999; 303: 349–80.

  6. 6

    Qiu J, Ni YH, Gong HX, Fei L, Pan XQ, Guo M, et al. Identification of differentially expressed genes in omental adipose tissues of obese patients by suppression subtractive hybridization. Biochem Biophys Res Commun 2007; 352: 469–78.

  7. 7

    Korkmaz CG, Korkmaz KS, Kurys P, Elbi C, Wang L, Klokk TI, et al. Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer. Oncogene 2005; 24: 4934–45.

  8. 8

    Moldes M, Lasnier F, Gauthereau X, Klein C, Pairault J, Feve B . Tumor necrosis factor-alpha-induced adipose-related protein (TIARP), a cell-surface protein that is highly induced by tumor necrosis factor-alpha and adipose conversion. J Biol Chem 2001; 276: 33938–46.

  9. 9

    Wellen KE, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, et al. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 2007; 129: 537–48.

  10. 10

    Wang B, Zhang M, Ni YH, Liu F, Fan HQ, Fei L, et al. Identification and characterization of NYGGF4, a novel gene containing a phosphotyrosine-binding (PTB) domain that stimulates 3T3-L1 preadipocytes proliferation. Gene 2006; 379: 132–40.

  11. 11

    Fried SK, Moustaid-Moussa N . Culture of adipose tissue and isolated adipocytes. Methods Mol Biol 2001; 155: 197–212.

  12. 12

    Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring) 2006; 14: 529–44.

  13. 13

    Tilg H, Moschen AR . Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–83.

  14. 14

    Winkler G, Kiss S, Keszthelyi L, Sápi Z, Ory I, Salamon F, et al. Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level. Eur J Endocrinol 2003; 149: 129–35.

  15. 15

    Xu H, Uysal KT, Becherer JD, Arner P, Hotamisligil GS . Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes 2002; 51: 1876–83.

  16. 16

    Hotamisligil GS, Budavari A, Murray D, Spiegelman BM . Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes: central role of tumor necrosis factor-alpha. J Clin Invest 1994; 94: 1543–9.

  17. 17

    Krogh-Madsen R, Plomgaard P, Møller K, Mittendorfer B, Pedersen BK . Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am J Physiol Endocrinol Metab 2006; 291: E108–14.

  18. 18

    Shojima N, Sakoda H, Ogihara T, Fujishiro M, Katagiri H, Anai M, et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cell. Diabetes 2002; 51: 1737–44.

  19. 19

    Finck BN, Johnson RW . Tumor necrosis factor (TNF)-alpha induces leptin production through the p55 TNF receptor. Am J Physiol Regul Integr Comp Physiol 2000; 278: R537–43.

  20. 20

    Hector J, Schwarzloh B, Goehring J, Strate TG, Hess UF, Deuretzbacher G, et al. TNF-alpha alters visfatin and adiponectin levels in human fat. Horm Metab Res 2007; 39: 250–5.

  21. 21

    Ajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, et al. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 2004: 53: 1671–9.

  22. 22

    Mukherjee SP, Lynn WS . Reduced nicotinamide adenine dinucle-otide phosphate oxidase in adipocyte plasma membrane and its activation by insulin. Possible role in the hormone's effects on adenylate cyclase and the hexose monophosphate shunt. Arch Biochem Biophys 1977; 184: 69–76.

  23. 23

    Krieger-Brauer HI, Kather H . Human fat cells possess a plasma membrane-bound H2O2-generating system that is activated by insulin via a mechanism bypassing the receptor kinase. J Clin Invest 1992; 89: 1006–13.

  24. 24

    Eriksson JW . Metabolic stress in insulin's target cells leads to ROS accumulation—a hypothetical common pathway causing insulin resistance. FEBS Lett 2007; 581: 3734–42.

Download references

Author information

Correspondence to Xiao-nan Li or Xi-rong Guo.

Additional information

Project supported by grants from the National Natural Science Foundation of China (No 30772364), the Natural Science Foundation of Jiangsu Province, China (No BK2007230), the Foundation of Ministry of Education, China (No 20070312001), and Nanjing Medical University (No 07NMUZ024).

Rights and permissions

Reprints and Permissions

About this article


  • six-transmembrane epithelial antigen of the prostate 4
  • obesity
  • tumor necrosis factor-α
  • adipose tissuess

Further reading