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25 ADIPOSITY AND PRO-ATHEROSCLEROTIC RESPONSES TO INNATE IMMUNE CHALLENGE IN HUMANS
  1. N. N. Mehta,
  2. P. D. Anderson,
  3. M. Wolfe,
  4. M. Rickels,
  5. B. Zemel*,
  6. C. Hinkle,
  7. L. Comiskey,
  8. J. Tabita-Martinez,
  9. R. Ahima,
  10. D. J. Rader,
  11. M. P. Reilly
  1. *Children's Hospital of Philadelphia, Philadelphia, 1University of Louisville
  2. Louisville VAMC

Abstract

Purpose A convergence of inflammatory and adipose signals has been proposed as a mechanism for metabolic syndrome and atherosclerosis. We hypothesized that adipose tissue may influence the response to acute inflammation in vivo in humans.

Method As part of a sixty-hour GCRC protocol of 20 healthy volunteers [50% male, 80% Caucasian, mean age 27.3 ± 4.8; 10 lean (BMI = 20.55 ± 1.75) and 10 overweight (BMI = 27.08 ± 0.88)], we examined peak responses in serial whole blood and adipose (subcutaneous fat biopsies) gene expression, and plasma hs-C reactive protein (hs-CRP) following intravenous administration of 3 ng/kg human research grade endotoxin.

Findings As expected, we observed increases (median fold increase and inter-quartile range) in whole blood mRNA expression of TNF alpha [8.8 fold (6.2-12.0)], IL-6 [3.8 (1.7-7.5)] and IL-10 [5.1 (2.4-7.7)], as well as plasma hs-CRP levels (mean peak hs-CRP 44.5 ± 21.7) following intravenous endotoxin (p<0.01 for all). Remarkably, there were marked increases in adipose mRNA levels of IL-6 [76.4 fold (45.4-154.3), p<0.001] as well as increases in TNF-alpha [5.3 (1.8-7.7), p<0.01], leptin [1.7 (1.4-2.2), p<0.05] and PPAR-alpha [2.8 (1.9-4.1), p<0.05]. Although not statistically significant in this small sample, peak plasma CRP levels (50.3 ± 27.0 versus 38.8 [138} 13.8, p = 0.1) tended to be higher and fold increase in whole blood IL-10 mRNA levels (3.74 versus 5.98, p = 0.3), an anti-inflammatory anti-atherosclerotic cytokine, tended to be lower in overweight subjects compared to lean.

Conclusions Our findings demonstrate, for the first time, that human adipose gene expression is regulated by activation of innate immunity in vivo, and preliminary analyses suggest that the response to an inflammatory stimulus may be influenced by the degree of adiposity. These observations provide novel insight into the role of adipose in promoting pro-atherosclerotic inflammatory responses in humans.

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