Leptin Receptor Isoforms mRNA Expression in Peripheral Blood Mononuclear Cells from Patients with Chronic Viral Hepatitis NIKOLAOS STEFANOU,* MARIA SATRA,* V ASSILIOS P APANIKOLAOU,* F ANI KALALA,  NIKOLAOS GATSELIS,à ANASTASIOS GERMENIS, GEORGE N. DALEKOS,à AND ASPASIA TSEZOU*,§ ,1 *University of Thessaly, Medical School, Department of Biology, 41222 Larissa, Greece;  University of Thessaly, Medical School, Department of Immunology, 41222 Larissa, Greece; àUniversity of Thessaly, Medical School, Department of Medicine, Academic Liver Unit, 41222 Larissa, Greece; and §University of Thessaly, Medical School, Laboratory of Cytogenetics and Medical Genetics, 41222 Larissa, Greece There is accumulating evidence that leptin has a pleiotropic role in hematopoiesis, immune response, fibrogenesis, and hepato- carcinogenesis. We investigated the expression of leptin and leptin receptor (OB-R) at the protein level by flow cytometry and also quantified by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) the two major leptin receptor isoforms (OB-Rl, OB-Rs) in peripheral blood mononuclear cells (PBMCs) of patients with hepatitis B (HBV; n ¼ 31), hepatitis C (HCV; n ¼ 34), and nonviral liver disease (n ¼ 25), and healthy controls (n ¼ 36), as well as in liver tissues of HBV (n ¼ 8), HCV (n ¼ 7), and healthy individuals (n ¼ 6). Serum leptin levels were measured in all participants (N ¼ 126). We observed significantly lower OB-Rl and OB-Rs mRNA levels in PBMCs of HBV and HCV patients compared with healthy controls and nonviral liver disease patients (P , 0.05). Flow cytometry analysis confirmed the real-time RT-PCR results. Expression of leptin and OB-Rl was significantly increased in viral hepatitis liver tissues compared with healthy tissues (P , 0.01). OB-Rl mRNA levels were not associated with hepatitis patients’ clinical status (inactive, chronic hepatitis, or cirrhosis). We also found decreased serum leptin in HBV and HCV patients compared with healthy individuals and the nonviral liver disease group. Leptin was expressed in 3 of 34 HCV (8.8%) and 19 of 25 (76%) nonviral liver disease patients. Moreover, expression of OB-Rl and OB-Rs were associated when all individuals were grouped together (r ¼ 0.78, P , 0.001). In conclusion, our findings may suggest the involvement of the leptin system in the immunopa- thology of chronic viral hepatitis. Exp Biol Med 231:1653–1663, 2006 Key words: leptin; leptin receptors; hepatitis B virus; hepatitis C virus; cirrhosis Introduction Leptin, the 16-kDa nonglycosylated protein product of the OB gene, is an essential hormone/cytokine that is secreted from adipocytes and links nutritional status with neuroendocrine and immune functions (1–4). As a hormone, leptin regulates appetite and energy homeostasis at the hypothalamic level by activating specific neuroendocrine pathways (2, 5, 6). As a cytokine, leptin affects thymic homeostasis and, similar to other proinflammatory cyto- kines, modulates the onset of immune responses (1, 7, 8). In humans, there are four isoforms of leptin receptor, generated by alternative splicing, which are membrane-spanning glycoproteins with cytoplasmic domains of varying length (9). The longest isoform (OB-Rl) is responsible for fully functional leptin signaling, while the shorter isoforms (OB- Rs) have truncated cytoplasmic domains with reduced signal transduction capabilities (10–12). Leptin receptors are expressed in a variety of peripheral tissues including the brain, liver, pancreas, placenta, lung, skeletal muscle, heart, hematopoietic cells, and peripheral blood mononuclear cells (PBMCs) (9, 13). It has been observed that leptin-deficient (ob/ob) and leptin receptor– deficient (db/db) mice present a complex syndrome that consists of abnormal reproductive function, hormonal imbalances, immune dysfunction, and reduced levels of peripheral T and B cells, suggesting a role for leptin in 1 To whom correspondence should be addressed at University of Thessaly, Faculty of Health Sciences, Medical School, Department of Biology, 22 Papakyriazi Street, 41222 Larissa, Greece. E-mail: atsezou@med.uth.gr Received September 7, 2005. Accepted April 10, 2006. 1653 1535-3702/06/23110-1653$15.00 Copyright Ó 2006 by the Society for Experimental Biology and Medicine