The prevalence of obesity has increased markedly over the last two decades in the United States and worldwide. Obesity is a major risk factor for diabetes type 2 and atherosclerosis, both of which are associated with inflammation. It has been suggested that obesity is a pro-oxidative and pro-inflammatory state which may be related to chronically increased macronutrient intake. Mononuclear cells (MNC) participate in atherogenicity in the arterial wall and also mediate inflammation in adipose tissue. This study will test the hypothesis that peripheral blood MNC in the obese are in a pro-inflammatory state when compared with those of normal lean subjects. Our first goal is to establish a link between obesity and the early steps of inflammation by showing an association between obesity and the pro-inflammatory transcription factor NFkappaB activation in MNC, which results in an increase in pro-inflammatory gene expressions (TNFalpha, IL-6, MIF and MMP-9). In addition, the differences in oxidative stress as reflected in reactive oxygen species (ROS) generation, NADPH oxidase, oxidized lipids, oxidized proteins and isoprostane between obese and lean subjects will be studied. Our second goal is to test the effect of weight loss on these inflammatory mediators and oxidative stress. Our third goal is to establish a correlation in the expression of these inflammatory mediators in MNC and adipose tissue from fat biopsies. Our fourth goal is to investigate whether the abnormal ischemic vasodilatation of the brachial artery known to occur in the obese will revert to normal following weight loss since abnormal vascular reactivity may be due to oxidative stress and inflammatory mediators like TNFalpha which reduce the availability of endothelial nitric oxide (NO), a vasodilator. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase known to be increased in obesity, will be measured before and after weight loss. In addition, the reduction of the inflammatory and oxidative stress mediators will be correlated with increased insulin sensitivity following weight loss. This study represents a unique opportunity to establish that 1) obesity is a pro-inflammatory and pro-oxidative stress state as observed in MNC and adipose tissue; 2) The reduction in inflammation and oxidative stress by weight loss may lead to improvement in abnormalities in vascular reactivity associated with obesity; 3) The reduction in oxidative stress and inflammation may in the long term potentially contribute to the prevention of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069805-04
Application #
7422291
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Jones, Teresa L Z
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$308,633
Indirect Cost
Name
State University of New York at Buffalo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Dandona, Paresh; Ghanim, Husam; Monte, Scott V et al. (2014) Increase in the mediators of asthma in obesity and obesity with type 2 diabetes: reduction with weight loss. Obesity (Silver Spring) 22:356-62
Monte, Scott V; Caruana, Joseph A; Ghanim, Husam et al. (2012) Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus. Surgery 151:587-93
Chaudhuri, Ajay; Ghanim, Husam; Vora, Mehul et al. (2012) Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab 97:198-207
Ghanim, Husam; Monte, Scott V; Sia, Chang Ling et al. (2012) Reduction in inflammation and the expression of amyloid precursor protein and other proteins related to Alzheimer's disease following gastric bypass surgery. J Clin Endocrinol Metab 97:E1197-201
Koduru, Sobha Rani; Achuthankutty, Smitha; Ghanim, Husam et al. (2012) Comment on: Lassenius et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care 2011;34:1809-1815. Diabetes Care 35:e17; author reply e18
Varanasi, Ajay; Bellini, Natalie; Rawal, Deepti et al. (2011) Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 165:77-84
Dandona, Paresh; Dhindsa, Sandeep (2011) Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab 96:2643-51
Ghanim, Husam; Sia, Chang Ling; Korzeniewski, Kelly et al. (2011) A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab 96:1409-14
Dandona, Paresh; Mohamed, Islam; Ghanim, Husam et al. (2011) Insulin suppresses the expression of amyloid precursor protein, presenilins, and glycogen synthase kinase-3beta in peripheral blood mononuclear cells. J Clin Endocrinol Metab 96:1783-8
Dhindsa, Sandeep; Furlanetto, Richard; Vora, Mehul et al. (2011) Low estradiol concentrations in men with subnormal testosterone concentrations and type 2 diabetes. Diabetes Care 34:1854-9

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