Atherosclerosis 200 (2008) 150–160 The relation of leptin and insulin with obesity-related cardiovascular risk factors in US adults Jared P. Reis a,b,∗ , Caroline A. Macera b , Deborah L. Wingard a , Maria Rosario G. Araneta a , Suzanne P. Lindsay b , Simon J. Marshall c a Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, 0607, La Jolla, CA 92093-0607, United States b Graduate School of Public Health, San Diego State University, San Diego, CA 92182, United States c Department of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA 92182, United States Received 20 August 2007; accepted 15 November 2007 Available online 26 December 2007 Abstract Previous studies of leptin with cardiovascular disease (CVD) risk factors have been limited by clinical samples or lack of representation of the general population. This cross-sectional study, designed to examine whether leptin or insulin may mediate the endogenous relation of obesity with metabolic, inflammatory, and thrombogenic cardiovascular risk factors, included 522 men and 514 women aged ≥40 years who completed a physical examination during the third National Health and Nutrition Examination Survey. Participants were free of existing CVD, cancer (except non-melanoma skin cancer), diabetes, or respiratory disease. In multivariable analyses adjusted for race/ethnicity and lifestyle factors, waist circumference (WC) was positively associated with blood pressure, triglyceride, LDL cholesterol, total cholesterol:HDL ratio, apolipoprotein B, C-reactive protein (CRP), and fibrinogen concentrations, and negatively associated with HDL cholesterol and apolipoprotein A1 levels. The associations of WC with the metabolic CVD risk factors were largely attenuated after adjustment for insulin levels, while the associations of WC with the inflammatory and thrombogenic factors (CRP and fibrinogen, respectively) were largely explained by adjustment for leptin concentrations. However, leptin levels were not independently associated with CRP and fibrinogen in men and CRP in women when adjusted for WC. Positive associations of leptin and insulin with fibrinogen in women, independent of WC, were noted. These results suggest that insulin may be an important mediator of the association of obesity with metabolic but not inflammatory or thrombogenic CVD risk factors, while leptin does not appear to influence cardiovascular risk through a shared association with these risk factors. However, we cannot rule out the possibility that leptin and insulin influence cardiovascular risk in women through independent effects on fibrinogen concentrations. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiovascular disease; Leptin; Risk factors; Inflammation 1. Introduction The prevalence of overweight and obesity are increas- ing dramatically in the US and worldwide [1,2]. Obesity and weight gain are strong independent predictors of inci- dent cardiovascular events [3,4] and predispose to numerous ∗ Corresponding author at: Department of Epidemiology and the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 2024 E Monument St, Suite 2-602, Baltimore, MD 21205, United States. Tel.: +1 410 502 6705; fax: +1 410 955 0476. E-mail address: jreis@jhsph.edu (J.P. Reis). risk factors for cardiovascular disease (CVD), including hypertension [5], dyslipidemia [6], and type 2 diabetes [7]. Randomized clinical trials have shown that weight reduction in obese adults can lead to short-term improvements in these metabolic conditions [8–11]. However, despite these con- sistent epidemiologic findings, the endogenous mechanism linking obesity with CVD remains largely elusive. Leptin is a hormone produced by the adipocyte and is widely recognized for its effects on food intake and energy balance. However, more recent research has implicated leptin in the development of CVD and as an independent predictor of incident cardiovascular events, in most, but not all studies 0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.11.015