ORIGINAL ARTICLE Adenovirus-Mediated Leptin Expression Normalises Hypertension Associated with Diet-Induced Obesity W. Zhang,*  1 S. Telemaque,à 2 R. A. Augustyniak,* 3 P. Anderson,à 4 G. D. Thomas,*  5 J. An,à 4 Z. Wang,* C. B. Newgard à 4 and R. G. Victor*  5 *Department of Internal Medicine/Hypertension Division, The University of Texas Southwestern Medical Center, Dallas, TX, USA.  The Donald W. Reynolds Cardiovascular Clinical Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA. àDepartment of Biochemistry and Gifford Laboratories for Diabetes Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA. The prevalence of obesity continues to increase worldwide, consti- tuting a major risk factor for cardiovascular morbidity and mortal- ity. However, the relationship between obesity and cardiovascular disease remains poorly understood. Leptin is a hormone secreted by adipocytes that acts centrally within the hypothalamus to both reduce appetite and increase thermogenesis through sympathetic activation (1, 2). Because leptin secretion increases in direct propor- tion to the level of adiposity, hyperleptinaemia is present during obesity in both humans and animals (3–6). Animal studies suggest that hyperleptinaemia may contribute to increases in arterial blood pressure (BP). High circulating leptin lev- els are present in murine models of genetic obesity (7) or leptin over-expression (8), both of which exhibit hypertension. In addition, chronic administration of leptin in both lean and obese mice (5) causes small increases in BP; whereas chronic leptin can cause either small increase or small decrease in BP in lean rats (9–11). More interestingly, the ob/ob mice, which have a mutation in the ob gene and are leptin deficient, exhibit a controversial phenotype: Journal of Neuroendocrinology Correspondence to: Weiguo Zhang, Nestle R&D Center Beijing, No. 5 Dijin Road, Haidian District, Beijing 100095, China (e-mail: rdzhangwe@nestle.com or weiguozha@yahoo.com). 1 Present address: Science & Research, Nestle R&D Center Beijing, Beijing, China. 2 Present address: Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 3 Present address: Departmnet of Biomedical Sciences, Oakland University William Beaumont School of Medicine, Rochester, MI, USA 4 Present address: Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC, USA. 5 Present address: The Cedars-Sinai Heart Institute, Los Angeles, CA, USA. In our previous study, moderate increases in plasma leptin levels achieved via administration of recombinant adenovirus containing the rat leptin cDNA were shown to correct the abnormal metabolic profile in rats with diet-induced obesity, suggesting that these animals had developed resistance to the metabolic effects of leptin, which could be reversed by leptin gene over- expression. However, the effect of this therapeutic strategy on blood pressure was not investi- gated. The present study aimed to determine whether a moderate increase of endogenous plasma leptin levels affected arterial blood pressure in rats with diet-induced obesity and hyper- tension. The major finding from the present study was that the natural rise in plasma leptin with weight-gain is insufficient to counterbalance high blood pressure associated with obesity, additional increases of circulating leptin levels with adenoviral leptin gene therapy led to nor- malisation of blood pressure in high-fat diet-induced obese and hypertensive rats. Mechanisti- cally, the reduction of blood pressure by leptin in obese rats was likely independent of a-adrenergic and acetylcholinergic receptor mediation. This is the first study to demonstrate that further increases in circulating leptin levels by leptin gene transfer during obesity could reduce blood pressure. Key words: arterial blood pressure, high-fat diet, hypertension, gene therapy, leptin, metabolic syndrome, obesity, recombinant adenovirus. doi: 10.1111/j.1365-2826.2010.01953.x Journal of Neuroendocrinology 22, 175–180 ª 2010 The Authors. Journal Compilation ª 2010 Blackwell Publishing Ltd Journal of Neuroendocrinology From Molecular to Translational Neurobiology