The prevalence of overweight/obesity has risen in the United States. The resulting increase in the metabolic syndrome affects approximately 25% of adults over age 20 and almost 50% over age 50. This state is characterized by a clustering of cardiovascular risk factors including visceral adiposity, insulin resistance, low HDL cholesterol and a systemic pro-inflammatory state that confers a marked increased risk of both type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). The molecular mechanisms linking obesity, the metabolic syndrome and ASCVD are poorly understood, however, innate immunity appears to play a proximal pathophysiological role. Acute activation of innate immunity during endotoxemia generates an inflammatory, metabolic and dyslipidemic response that is remarkably similar to metabolic syndrome. Adipocytes, like monocytes, can mediate a robust inflammatory response to acute stresses. Adipose tissue produces a variety of adipocytokines (TNF(, IL6, leptin, adiponectin and resistin) that mediate chronic inflammatory and proatherosclerotic responses in the metabolic syndrome. In animals, obesity amplifies the inflammatory and metabolic responses to endotoxemia but the effect on evoked inflammation in humans has not been addressed. Potential proatherosclerotic mechanisms in endotoxemia and the metabolic syndrome include cytokine signaling, dyslipidemia, insulin resistance and oxidant stress. Changes in lipoproteins, particularly HDL, may reduce macrophage cholesterol efflux and the anti-atherosclerotic reverse cholesterol transport pathway. The effect of endotoxemia or the metabolic syndrome on specific macrophage cholesterol efflux pathways in humans is unknown. We and others have used controlled administration of endotoxin in humans to study the pathophysiology of acute inflammation and its modulation in vivo. We propose to use this model to (1) systematically assess proatherosclerotic pathways during activation of innate immunity in the metabolic syndrome, (2) characterize the effect of innate immune activation on specific macrophage cholesterol efflux pathways and (3) determine the capacity of a candidate metabolic syndrome therapy, the PPARg agonist Rosiglitazone, to modulate pro-atherosclerotic response in the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073278-04
Application #
7059932
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F1))
Program Officer
Ershow, Abby
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$319,682
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Mehta, Nehal N; McGillicuddy, Fiona C; Anderson, Paul D et al. (2010) Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes 59:172-81

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