CLINICAL STUDY Increased T-helper interferon-g-secreting cells in obese children Lucia Pacifico 1,2 , Livia Di Renzo 3 , Caterina Anania 1 , John F Osborn 4 , Flora Ippoliti 3 , Elisa Schiavo 1 and Claudio Chiesa 1,2 Departments of 1 Pediatrics, 3 Experimental Medicine and 4 Public Health Science, La Sapienza University of Rome, Viale Regina Elena, 324 00161-Rome, Italy and 2 National Research Council, Rome, Italy (Correspondence should be addressed to L Pacifico; Email: Lucia.Pacifico@Uniroma1.it) Abstract Objective: Leptin, an adipocyte-secreted hormone, has emerged as a potential candidate for the link between obesity and the proinflammatory state. Specifically, leptin modulates T-helper (Th) cells toward a Th1 phenotype, with the secretion of proinflammatory cytokines. The aim of this study was to evaluate the Th1/Th2 balance in obese children and its relation with hormonal and metabolic features. Study design: In 50 obese children and 20 control children, we measured the CD4-positive Th cells that secrete interferon (IFN)-g or interleukin (IL)-2 (taken as an index of Th1 cells), and IL-4 (taken as an index of Th2 cells) as well as serum glucose, insulin, insulin resistance (IR) index (as homeostasis model assessment model (HOMA)), lipid profile, aminotransferases, leptin and ghrelin. Obese children also underwent dual energy X-ray absorptiometry scan measurements, and liver ultra- sound scanning. Results: Geometric mean percentages of IL-2- and IL-4-CD4 secreting cells in obese children were not significantly different from those found in control children. However, the geometric mean percentage of CD4-positive T cells secreting IFN-g was significantly higher in the obese than in the control (P , 0.0001, t-test) group. Within the entire group of study children, the percentage of IFN-g-positive cells was positively associated with leptin (P ¼ 0.002), insulin (P , 0.00 005), and HOMA-IR values (P , 0.00005). However, when these associations were restricted to the group of obese subjects, insulin and HOMA-IR values, but not leptin, retained statistical significance. Yet, in the obese group, the percentage of IFN-g-positive cells was associated with nonalcoholic steatohepatitis (NASH) (P ¼ 0.001), but not with body mass index-standard deviation score and total body fat mass. Conclusions: In obese children, a shift to Th1-cytokine profile dominated by the production of IFN-g is related to insulin resistance as well as to NASH independently of anthropometric features and other metabolic characteristics. The prevalent Th1 pattern of secreted cytokines may be regarded as a mechanism contributing to inflammation in obesity. European Journal of Endocrinology 154 691–697 Introduction Obesity may be a low-grade, systemic, inflammatory disease. Obese children and adults have high circulat- ing levels of both acute phase reactant proteins and inflammatory cytokines, which are closely associated with cardiovascular risk factors and cardiovascular and noncardiovascular causes of death (1). This may explain the increased risk of diabetes, heart disease and many other chronic diseases in the obese. Among cells of the immune system, T cells play a major role in the inflammatory response. Key regulators of this response are a subset of T cells called CD4-positive T helper (Th) cells, which can be further differentiated into two subtypes, Th1 and Th2 cells, by the different cytokines they produce (2). The appropriate regulation of Th cell immunity is critical in the control and prevention of diverse diseases. Leptin, an adipocyte-secreted hormone with structural similarity to cytokines, has emerged as a potential can- didate for the link between obesity and the proinflam- matory state. Studies in animal (3) and human (4) models of congenital complete leptin deficiency, which are characterized by morbid obesity and immune dysfunction, suggest a potentially important role for leptin in regulating immune function. More specifically, European Journal of Endocrinology (2006) 154 691–697 ISSN 0804-4643 q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02138 Online version via www.eje-online.org