Current Pharmaceutical Design, 2008, 14, 2699-2706 2699 1381-6128/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Body Composition and -174G/C Interleukin-6 Promoter Gene Polymor- phism: Association with Progression of Insulin Resistance in Normal Weight Obese Syndrome L. Di Renzo 1,4 , A. Bertoli 2 , M. Bigioni 1 , V. Del Gobbo 3 , M.G. Premrov 3 , V. Calabrese 5 , N. Di Daniele 2 , A. De Lorenzo 1,4, * 1 Department of Neuroscience, Division of Human Nutrition, University of Tor Vergata, Via Montpellier 1, I-00133 Rome, Italy; 2 Department of Internal Medicine, University Hospital Tor Vergata, Via Montpellier 1, I-00133 Rome, It- aly; 3 Department of Experimental Medicine and Biochemical Sciences, Division of Immunology University of Tor Ver- gata, Via Montpellier 1, I-00133 Rome, Italy; 4 I.N.Di.M, National Institute for Mediterranean Diet and Nutrigenomic, Reggio Calabria, Italy and 5 Biochemistry and Molecular Biology Section, Department of Chemistry, University of Ca- tania, Viale Andrea Doria 6, 95125 Catania Italy Abstract: Insulin resistance and obesity are intimately related to a chronic low grade systemic inflammation. Interleukin- 6 (IL-6) may influence the pathogenesis of obesity-related diseases. The aim of this study is to investigate the effect of body’s fat mass on the relationships between -174G/C IL-6 promoter gene polymorphism, IL-6 circulating level and insu- lin resistance. A population of 150 Caucasian women was studied, subdivided according to their body composition in non-obese (NW), Normal Weight Obese (NWO) and preobese-obese (OB). The NWO subjects were found in an intermediate position between the NW and OB subjects in terms of body weight, fat mass percentage (FM%), abdominal FAT%, hs-CRP and plasma triglyceride level. Fasting plasma IL-6 concentration was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) in all subjects analyzed (P=0.0014). In NWO and OB women a significantly increased IL-6 mean value was observed compared with NW sub- jects. In G/G population, the IL-6 plasma level of NWO and OB was significantly higher with respect to NW. No signifi- cant differences of IL-6 concentrations were observed in the three groups carrying G/C genotype. NWO and OB women homozygous for the allele C have significantly lower value of IL-6 with respect to NW subjects. IL-6 concentration was positively correlated with FM% in G/G (R 2 =0.397, P<0.001) and was negatively correlated in C/C (R 2 =0.459, P=0.002). No significant correlation was observed in G/C genotype (R 2 =0.041, P=0.173). In conclusion our study confirms that, at least in Italian Caucasian females, the FM% is a major determinant of an in- crease in IL-6 production and insulin resistance. -174 G/C IL-6 promoter polymorphism represents a marker which could help to identify, time in advance, “vulnerable” individuals at risk of age and obesity related diseases. Key Words: IL-6 -174 G/C promoter polymorphism, obesity, insulin resistance, body composition, obesity related diseases. INTRODUCTION Obesity and glucose metabolism are intimately related to a low grade systemic inflammation, involving a number of pro-inflammatory cytokines produced by many cell types that also appear to be major regulators of adipose tissue me- tabolism [1,2]. IL-6 plays a central role in coordinating the mechanism of pro-inflammation pathway [3]. There are some evidences suggesting the implication of a network of cytokines for the development of metabolic disorders, as type 2 diabetes and cardiovascular diseases [4,5]. It is well recognized that obesity and diabetes, conditions associated with an increased CVD risk, are also correlated with a chronic low-grade activation of the immune system *Address correspondence to this author at the Department of Neuroscience, Division of Human Nutrition University of Tor Vergata, Via Montpellier 1, I-00133 Rome, Italy and I.N.Di.M., National Institute for Mediterranean Diet and Nutrigenomic, Reggio Calabria, Italy; Tel/Fax: +39 0672596415; E-mail: delorenzo@uniroma2.it [6]. The chronic low grade sub clinical inflammation has been proposed as a part of insulin-resistance syndrome and a large amount of data suggests a pathogenetic role in diabetes and diabetes mellitus associated CVD [1, 7, 8]. Some recent papers demonstrated that IL-6 levels are associated to different clinical outcomes following coronary revascularization surgery [9]. Adipose tissue is not only a major source of IL-6 produc- tion, but may be also responsive to this cytokine. Secreted IL-6 may act on adipocytes autocrinally or paracrinally [1, 2]. In obese population such as those with impaired glucose tolerance or type 2 diabetes mellitus, increased adiposity may result in increased IL-6 product [10,11]. On the other hand several lines of evidence suggest that obesity can not be characterized only by BMI. Percentage fat mass and fat distribution may be different in subjects with