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Innate Immunity Modulates Adipokines in Humans

The Cardiovascular Institute (P.D.A., N.N.M., M.L.W., C.C.H., L.P., L.L.C., J.T.-M., M.P.R.) and the Institute for Translational Medicine and Therapeutics (M.L.W., L.P., M.P.R.), Institute of Diabetes Obesity and Metabolism (M.R.R., R.S.A., M.P.R.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160; Department of Mathematics (K.F.S.), Georgetown University, Washington, D.C. 20057; and University of Washington School of Medicine (P.D.A.), Seattle, Washington 98195

Address all correspondence and requests for reprints to: Muredach P. Reilly, Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160. E-mail: muredach{at}spirit.gcrc.upenn.edu.

Context: Chronic inflammation converges in type 2 diabetes and atherosclerosis. Modulation of adipokine signaling by innate immunity in humans is of considerable interest given the role of adipokines in insulin resistance and atherosclerosis.

Objective: The aim of the study was to examine effects of low-grade endotoxemia, a model of human inflammation, on adipokines in vivo.

Design/Setting: An open-label, placebo-controlled, fixed-sequence clinical study was conducted at a General Clinical Research Center.

Patients: There were 20 healthy male (50%) and female volunteers aged 18–40 yr.

Intervention: Serial blood sampling and adipose biopsies were performed for 24 h before and after iv bolus endotoxin [lipopolysaccharide (LPS), 3 ng/kg].

Main Outcome Measures: We measured plasma leptin, adiponectin, resistin, soluble leptin receptor, cytokines, insulin, and glucose; distribution of adiponectin among multimeric complexes; whole blood, monocyte and adipose mRNA for adipokines and their receptors.

Results: LPS induced fever, blood, and adipose TNF and IL-6 and increased homeostasis model assessment of insulin resistance. These were associated with increases in plasma leptin (from 4.1 ± 1.1 to 6.1 ± 1.9 ng/ml in men; 21.1 ± 4.4 to 27.4 ± 4.7 ng/ml in women; P < 0.005), doubling of the leptin:soluble leptin receptor ratio, and marked induction of whole blood resistin mRNA (13.7 ± 7.3-fold; P < 0.001) and plasma resistin (8.5 ± 2.75 to 43.2 ± 15.3 ng/ml; P < 0.001). Although total adiponectin levels and low and high molecular weight adiponectin complexes were unaltered by LPS treatment, whole blood mRNA for adiponectin receptors 1 (49%; P < 0.005) and 2 (65%; P < 0.001) was suppressed.

Conclusions: Modulation of adipokine signaling may contribute to the insulin resistant, atherogenic state associated with human inflammatory syndromes. Targeting of individual adipokines or their upstream regulation may prove effective in preventing acute and chronic inflammation-related metabolic complications.

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