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Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells

International Journal of Obesity volume 31, pages 87–96 (2007)Cite this article

Abstract

Objective:

Human adenovirus Ad-36 causes adiposity in animal models and enhances differentiation and lipid accumulation in human and 3T3-L1 preadipocytes, which may, in part, explain the adipogenic effect of Ad-36. We determined the consequences of Ad-36 infection on leptin and glucose metabolism in fat cells.

Design:

3T3-L1 preadipocytes were used to determine the effect of infection by human adenoviruses Ad-36, Ad-2, Ad-9 and Ad-37 on leptin secretion and lipid accumulation. Rat primary adipocytes were used to determine the effect of Ad-36 infection on leptin secretion and glucose uptake in vitro. Furthermore, the effect of Ad-36 on expressions of leptin and selected genes of de novo lipogenesis pathway of visceral adipose tissue were compared ex vivo, between Ad-36 infected and uninfected control rats.

Results:

Ad-36 suppressed the expression of leptin mRNA in 3T3-L1 cells by approximately 58 and 52% on days 3 and 5 post-infection, respectively. Leptin release normalized to cellular lipid content was 51% lower (P<0.002) in the Ad-36 infected 3T3-L1 cells. Lipid accumulation was significantly greater and leptin secretion was lower for the 3T3-L1 cells infected with other human adenoviruses Ad-9, Ad-36, or Ad-37. Whereas, human adenovirus Ad-2 did not influence cellular lipid accumulation or the leptin release. In rat primary adipocytes, Ad-36 reduced leptin release by about 40% in presence of 0.48 (P<0.01) or 1.6 nM insulin (P<0.05) and increased glucose uptake by 93% (P<0.001) or 18% (P<0.05) in presence of 0 or 0.48 nM insulin, respectively. Next, the adipose tissue of Ad-36 infected rats showed two to fivefold lower leptin mRNA expression, and 1.6- to 21-fold greater expressions for acetyl Co-A carboxylase-1 and 1.2- to 6.3-fold greater expressions for fatty acid synthase, key genes of de novo lipogenesis, compared to the uninfected weight and adiposity matched controls.

Conclusion:

The in vitro and ex vivo studies show that Ad-36 modulates adipocyte differentiation, leptin production and glucose metabolism. Whether such a modulation contributes to enhanced adipogenesis and consequent adiposity in Ad-36 infected animals or humans needs to be determined.

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References

  1. Sclafani A . Animal models of obesity: classification and characterization. Int J Obes 1984; 8: 491–508.

    CAS  PubMed  Google Scholar 

  2. Astrup A, Lundsgaard C, Stock MJ . Is obesity contagious? Int J Obes Relat Metab Disord 1998; 22: 375–376.

    Article  CAS  PubMed  Google Scholar 

  3. Rossner S . Can obesity be an infectious disease? Lakartidningen 2005; 102: 1896–1898.

    PubMed  Google Scholar 

  4. Dhurandhar NV . Infectobesity: obesity of infectious origin. J Nutr 2001; 131: 2794S–2797S.

    Article  CAS  PubMed  Google Scholar 

  5. So PW, Herlihy AH, Bell JD . Adiposity induced by adenovirus 5 inoculation. Int J Obes Relat Metab Disord 2005; 29: 603–606.

    Article  CAS  Google Scholar 

  6. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew G, Cook ME, Atkinson RL . Transmissibility of adenovirus-induced adiposity in a chicken model. Int J Obes Relat Metab Disord 2001; 25: 990–996.

    Article  CAS  PubMed  Google Scholar 

  7. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew GF, Cook ME, Atkinson RL . Increased adiposity in animals due to a human virus. Int J Obes Relat Metab Disord 2000; 24: 989–996.

    Article  CAS  PubMed  Google Scholar 

  8. Dhurandhar NV, Whigham LD, Abbott DH, Schultz-Darken NJ, Israel BA, Bradley SM et al. Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys. J Nutr 2002; 132: 3155–3160.

    Article  CAS  PubMed  Google Scholar 

  9. Dhurandhar NV, Augustus AS, Atkinson RL . Evidence of an association of a virus with obesity in humans. FASEB J 1997; 3: A230.

    Google Scholar 

  10. Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB et al. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes Relat Metab Disord 2005; 29: 281–286.

    Article  CAS  Google Scholar 

  11. Vangipuram SD, Sheele J, Atkinson RL, Holland TC, Dhurandhar NV . A human adenovirus enhances preadipocyte differentiation. Obes Res 2004; 12: 770–777.

    Article  CAS  PubMed  Google Scholar 

  12. Havel PJ . Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. Curr Opin Lipidol 2002; 13: 51–59.

    Article  CAS  PubMed  Google Scholar 

  13. Havel PJ . Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 2004; 53 (Suppl 1): S143–S151.

    Article  CAS  PubMed  Google Scholar 

  14. Chen X, Hausman DB, Dean RG, Hausman GJ . Differentiation-dependent expression of obese (ob) gene by preadipocytes and adipocytes in primary cultures of porcine stromal-vascular cells. Biochim Biophys Acta 1997; 1359: 136–142.

    Article  CAS  PubMed  Google Scholar 

  15. Ahima RS, Flier JS . Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327–332.

    Article  CAS  PubMed  Google Scholar 

  16. Huan JN, Li J, Han Y, Chen K, Wu N, Zhao AZ . Adipocyte-selective reduction of the leptin receptors induced by antisense RNA leads to increased adiposity, dyslipidemia, and insulin resistance. J Biol Chem 2003; 278: 45638–45650.

    Article  CAS  PubMed  Google Scholar 

  17. Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R et al. Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci USA 2004; 101: 2058–2063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang MY, Lee Y, Unger RH . Novel form of lipolysis induced by leptin. J Biol Chem 1999; 274: 17541–17544.

    Article  CAS  PubMed  Google Scholar 

  19. Zhou YT, Wang ZW, Higa M, Newgard CB, Unger RH . Reversing adipocyte differentiation: implications for treatment of obesity. Proc Natl Acad Sci USA 1999; 96: 2391–2395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Komers R, Vrana A . Thiazolidinediones--tools for the research of metabolic syndrome X. Physiol Res 1998; 47: 215–225.

    CAS  PubMed  Google Scholar 

  21. Lagace DC, McLeod RS, Nachtigal MW . Valproic acid inhibits leptin secretion and reduces leptin messenger ribonucleic acid levels in adipocytes. Endocrinology 2004; 145: 5493–5503.

    Article  CAS  PubMed  Google Scholar 

  22. Verges B . Clinical interest of PPARs ligands. Diabetes Metab 2004; 30: 7–12.

    Article  CAS  PubMed  Google Scholar 

  23. Perez C, Fernandez-Galaz C, Fernandez-Agullo T, Arribas C, Andres A, Ros M et al. Leptin impairs insulin signaling in rat adipocytes. Diabetes 2004; 53: 347–353.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang HH, Kumar S, Barnett AH, Eggo MC . Intrinsic site-specific differences in the expression of leptin in human adipocytes and its autocrine effects on glucose uptake. J Clin Endocrinol Metab 1999; 84: 2550–2556.

    CAS  PubMed  Google Scholar 

  25. Ramirez-Zacarias JL, Castro-Munozledo F, Kuri-Harcuch W . Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry 1992; 97: 493–497.

    Article  CAS  PubMed  Google Scholar 

  26. Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH et al. Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes. Endocrinology 1998; 139: 551–558.

    Article  CAS  PubMed  Google Scholar 

  27. Landt M, Gingerich RL, Havel PJ, Mueller WM, Schoner B, Hale JE et al. Radioimmunoassay of rat leptin: sexual dimorphism reversed from humans. Clin Chem 1998; 44: 565–570.

    CAS  PubMed  Google Scholar 

  28. Moreno-Aliaga MJ, Stanhope KL, Havel PJ . Transcriptional regulation of the leptin promoter by insulin-stimulated glucose metabolism in 3t3-l1 adipocytes. Biochem Biophys Res Commun 2001; 283: 544–548.

    Article  CAS  PubMed  Google Scholar 

  29. Pasarica M, Ou Lang H, Mahida M, Yu M, Mohankumar S, Mohankumar P et al. Human Adenovirus Ad-36 induces adiposity and increases insulin sensitivity. Obes Res 2004; 12: A122.

    Google Scholar 

  30. Igel M, Taylor BA, Phillips SJ, Becker W, Herberg L, Joost HG . Hyperleptinemia and leptin receptor variant Asp600Asn in the obese, hyperinsulinemic KK mouse strain. J Mol Endocrinol 1998; 21: 337–345.

    Article  CAS  PubMed  Google Scholar 

  31. Wigand R, Gelderblom H, Wadell G . New human adenovirus (candidate adenovirus 36), a novel member of subgroup D. Arch Virol 1980; 64: 225–233.

    Article  CAS  PubMed  Google Scholar 

  32. MacDougald OA, Hwang CS, Fan H, Lane MD . Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes. Proc Natl Acad Sci USA 1995; 92: 9034–9037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. De Vos P, Lefebvre AM, Miller SG, Guerre-Millo M, Wong K, Saladin R et al. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest 1996; 98: 1004–1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hwang CS, Loftus TM, Mandrup S, Lane MD . Adipocyte differentiation and leptin expression. Annu Rev Cell Dev Biol 1997; 13: 231–259.

    Article  CAS  PubMed  Google Scholar 

  35. Yoshida T, Monkawa T, Hayashi M, Saruta T . Regulation of expression of leptin mRNA and secretion of leptin by thyroid hormone in 3T3-L1 adipocytes. Biochem Biophys Res Commun 1997; 232: 822–826.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Y, Guo KY, Diaz PA, Heo M, Leibel RL . Determinants of leptin gene expression in fat depots of lean mice. Am J Physiol Regul Integr Comp Physiol 2002; 282: R226–R234.

    Article  CAS  PubMed  Google Scholar 

  37. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292–295.

    Article  CAS  PubMed  Google Scholar 

  38. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS . Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1: 1311–1314.

    Article  CAS  PubMed  Google Scholar 

  39. Lonnqvist F, Nordfors L, Jansson M, Thorne A, Schalling M, Arner P . Leptin secretion from adipose tissue in women. Relationship to plasma levels and gene expression. J Clin Invest 1997; 99: 2398–2404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guo KY, Halo P, Leibel RL, Zhang Y . Effects of obesity on the relationship of leptin mRNA expression and adipocyte size in anatomically distinct fat depots in mice. Am J Physiol Regul Integr Comp Physiol 2004; 287: R112–R119.

    Article  CAS  PubMed  Google Scholar 

  41. Moller N, O'Brien P, Nair KS . Disruption of the relationship between fat content and leptin levels with aging in humans. J Clin Endocrinol Metab 1998; 83: 931–934.

    CAS  PubMed  Google Scholar 

  42. Scholz GH, Englaro P, Thiele I, Scholz M, Klusmann T, Kellner K et al. Dissociation of serum leptin concentration and body fat content during long term dietary intervention in obese individuals. Horm Metab Res 1996; 28: 718–723.

    Article  CAS  PubMed  Google Scholar 

  43. Whigham LD, Israel BA, Atkinson RL . Adipogenic potential of multiple human adenoviruses in vivo and in vitro in animals. Am J Physiol Regul Integr Comp Physiol 2006; 290 (1): R190–R194.

    Article  CAS  PubMed  Google Scholar 

  44. Mueller WM, Stanhope KL, Gregoire F, Evans JL, Havel PJ . Effects of metformin and vanadium on leptin secretion from cultured rat adipocytes. Obes Res 2000; 8: 530–539.

    Article  CAS  PubMed  Google Scholar 

  45. Leibel RL . The role of leptin in the control of body weight. Nutr Rev 2002; 60: S15–S19; discussion S68–S84, 85–17.

    Article  PubMed  Google Scholar 

  46. Bernard A, Cohen R, Khuth ST, Vedrine B, Verlaeten O, Akaoka H et al. Alteration of the leptin network in late morbid obesity induced in mice by brain infection with canine distemper virus. J Virol 1999; 73: 7317–7327.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhou YT, Shimabukuro M, Lee Y, Koyama K, Higa M, Ferguson T et al. Enhanced de novo lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats: role in the pathogenesis of lipotoxic diabetes. Diabetes 1998; 47: 1904–1908.

    Article  CAS  PubMed  Google Scholar 

  48. Buettner R, Bollheimer LC, Zietz B, Drobnik W, Lackner K, Schmitz G et al. Definition and characterization of relative hypo- and hyperleptinemia in a large Caucasian population. J Endocrinol 2002; 175: 745–756.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by funds from the William Hardy Endowment for Obesity Research, and NIH Grant 1R01 DK066164-01 to NVD.

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Authors and Affiliations

  1. Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA

    S D Vangipuram, M Yu, J Tian, M Pasarica & A R Heydari

  2. Department of Nutrition, University of California, Davis, CA, USA

    K L Stanhope & P J Havel

  3. Pennington Biomedical Research Center, Baton Rouge, LA, USA

    M Pasarica & N V Dhurandhar

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  1. S D Vangipuram
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Correspondence to N V Dhurandhar.

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Vangipuram, S., Yu, M., Tian, J. et al. Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells. Int J Obes 31, 87–96 (2007). https://doi.org/10.1038/sj.ijo.0803366

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