The aim of this work was to analyze vascular remodeling and mechanical alterations in mesenteric arteries in a model of diet-induced obesity in mice, as well as the impact of adipokine dysregulation in those changes. Four-week old CB57BL/6J male mice were assigned either to a control (10% kcal from fat) or to a high-fat (HF) diet (45% kcal from fat). After 32 weeks of diet, HF animals weighed 30% more than controls (p<0.001). Moreover, HF animals exhibited an increase in leptin but a reduction in adiponectin plasma levels. Studies of arterial structure and mechanics, performed by pressure myography did not reveal a significant vascular remodeling in HF mice. However, we observed a significant increase in arterial stiffness in HF mice, as assessed by b-values (obtained from stress-strain relationship; LF=2.4±0.5 vs HF=5.3±0.8, p<0.05) and pulse wave velocity values (LF=3.4±0.1 vs HF=3.9±0.1; p<0.05). Moreover, though we did not find differences in elastin content, a significant reduction in fenestrae number with HF diet together with a significant increase in collagen I amount (p<0.05) were observed. Positive and negative correlations were found between b-values and leptin or adiponectin levels, respectively (p<0.01). In conclusion, these data demonstrate that HF diet accounts for an increase in arterial stiffness that is associated with adipokine dysregulation. Supported by grants from Ministerio de Ciencia e Investigación (BFU2011-25303), Ministerio de Economía y Competitividad (SAF2009-09714, SAF2011-25303, BFU2012-35353), Grupos Universidad Complutense de Madrid (UCM;GR-921641), Fundación Universitaria San Pablo-CEU, Fundación Mutua Madrileña and Sociedad para el Estudio de la Salud Cardiometabólica (SESCAMET).