Article Text

  1. P. D. Anderson1,2,
  2. N. N. Mehta1,
  3. M. L. Wolfe1,
  4. K. McMahon1,
  5. C. Hinkle1,
  6. L. Comiskey1,
  7. J. Tabita-Martinez1,
  8. K. Sellers1,
  9. R. S. Ahima1,
  10. D. J. Rader1,
  11. M. P. Reilly1
  1. 1University of Pennsylvania Medical School, Philadelphia, PA
  2. 2Sarnoff Endowment for Cardiovascular Science


Purpose A convergence of innate immune and adipose signals is thought to promote metabolic syndrome and atherosclerosis. Indeed, septicemia and experimental endotoxemia induce insulin resistance and metabolic dyslipidemia. However, the role of innate immunity in regulating adipokines, key modulators of insulin resistance and atherosclerosis, is poorly defined in humans.

Method A human endotoxemia model was used to examine the impact of activation of innate immunity on resistin, adiponectin and leptin pathways in vivo. Serial whole blood and adipose (subcutaneous biopsies) gene expression (quantitative PCR) as well as plasma levels of adipokines were measured for 24 hours prior to and following intravenous administration of 3 ng/kg endotoxin (LPS) in 20 healthy human volunteers (50% male, 80% Caucasian, mean age 27.3 ± 4.8, inpatient GCRC protocol). Repeated measures analysis of variance was applied to the data.

Findings Whole blood resistin mRNA levels (13.7 ± 7.3 fold; F statistic = 47.3, p<0.001) and plasma resistin levels (from 8.5 ± 2.75 to 43.2 ± 15.3 ng/mL at 12 hours post LPS; F statistic = 72.1, p<0.001) increased markedly during endotoxemia. Remarkably, adipose resistin mRNA levels were barely detectable. In contrast, we found no change in plasma adiponectin levels (baseline 10.7 ± 5.5 μg/mL), an absence of adiponectin mRNA in whole blood, and a small increase in adipose adiponectin mRNA levels (2.5 ± 1.30 fold). However, there were marked decreases in whole blood mRNA levels of adiponectin receptors (49% reduction in R1 at 24 hours; F statistic = 8.4, p<0.001, and 65% reduction in R2 at 4 hours; F statistic = 21.3, p<0.001). Finally, both adipose leptin mRNA levels (1.72 fold at 12 hours; F statistic = 3.94, p<0.05) and plasma leptin levels (1.53 fold at 16 hours; F statistic = 3.3, p<0.05) increased modestly.

Conclusions Endotoxemia induces specific and differential effects on adipokine signaling in humans. Strikingly, resistin appears to be a leukocyte, but not adipose, derived inflammatory cytokine in humans, which is vastly increased in response to LPS. In contrast, adiponectin levels are unchanged during endotoxemia, but expression of both adiponectin receptor subtypes is decreased, consistent with an attenuation of adiponectin insulin sensitizing and anti-atherosclerotic signaling in vivo.

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