SHORT COMMUNICATION Leptin is essential in maintaining normal vascular compliance independent of body weight G Sikka 1 , R Yang 2 , S Reid 2,3 , A Benjo 1 , N Koitabashi 2 , A Camara 1 , E Baraban 1 , CP O’Donnell 4 , DE Berkowitz 1 and LA Barouch 2 1 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3 Howard University College of Medicine, Washington, DC, USA and 4 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA The adipocytokine leptin centrally regulates body weight by enhancing metabolic rate and signaling satiety, but it also has wide- ranging peripheral effects. Leptin receptors are expressed on vascular smooth muscle cells and have a role in maintaining vascular tone. We investigated the vascular effects of leptin repletion or calorie restriction on leptin-deficient mice (ob/ob) and a leptin antagonist on wild-type (WT) mice. Aortic compliance was assessed by the measurement of pulse wave velocity by noninvasive Doppler; blood pressure was measured by left ventricular catheterization. We found that ob/ob mice have much stiffer aortas than WT mice and that reduction in aortic stiffness was greater in ob/ob mice treated with leptin vs calorie restriction, despite similar weight loss. Interestingly, treating WT mice with a leptin antagonist increases aortic stiffness with no change in weight. Thus, we conclude that leptin is essential for maintaining normal aortic compliance independent of body weight. International Journal of Obesity (2010) 34, 203–206; doi:10.1038/ijo.2009.208; published online 6 October 2009 Keywords: leptin; vascular compliance; aorta; pulse wave velocity Introduction The central vs peripheral roles of leptin have been intensely debated. Serum levels of this adipokine are proportional to fat mass, acting to suppress satiety through the hypothala- mus and enhance overall metabolism by modulating energy expenditure. 1 Elevated circulating leptin is associated with vascular calcification, 2 increased blood pressure 3 and decreased vascular compliance; 4 however, these effects may be attributable to leptin resistance rather than leptin excess itself. 5 Conversely, leptin provides beneficial receptor-mediated effects on vascular tone and growth. Both long (Ob-Rb) and short (Ob-Ra) isoforms of leptin receptors are highly expressed in endothelial 6 and vascular smooth muscle cells, 7 with leptin stimulation enhancing nitric oxide production. Angiogenesis is accelerated with hyperleptinemia, 6 and improved endothelial function is evident in ex vivo experi- ments in ob/ob mice. 8 On the basis of potential vascular benefit of intact leptin signaling beyond its primary effect on body weight, we examined aortic compliance and blood pressure in lean and obese mice with disrupted leptin signaling. Materials and methods Animals We studied five groups (n ¼ 5–9/group) of 7- to 9-month-old ob/ob and C57BL/6 (WT) mice (Jackson Laboratory, Bar Harbor, ME, USA): control (phosphate-buffered saline- infused) ob/ob (OB), leptin-treated ob/ob (0.3 mg/kg/day; Amgen, Thousand Oaks, CA, USA; OB-LT) and calorie- restricted ob/ob (OB-CR), all treated for 4 weeks, and control (phosphate-buffered saline-infused) WT and leptin-antago- nist-treated WT (leptin triple mutant L39A/D40A/F41A, 0.3 mg/kg/day; Protein Laboratories, Rehovot, Israel; WT-LA) treated for 2 weeks. Drugs were delivered through osmotic pumps (Alzet, Cupertino, CA, USA) as previously described. 8 OB-CR were calorie restricted to achieve weight loss similar to OB-LT. 8 A second set of animals (10–12 weeks Received 3 April 2009; revised 6 August 2009; accepted 22 August 2009; published online 6 October 2009 Correspondence: Dr LA Barouch, Division of Cardiology, Johns Hopkins University School of Medicine, Ross Research Building 1050, 720 Rutland Avenue, Baltimore, MD 21205, USA. E-mail: Barouch@jhmi.edu International Journal of Obesity (2010) 34, 203–206 & 2010 Macmillan Publishers Limited All rights reserved 0307-0565/10 $32.00 www.nature.com/ijo