Progression of cardiovascular and endocrine dysfunction in a rabbit model of obesity

In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n¼23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP p80mmHg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2mmHg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4mmHg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline 480mmHg. Plasma concentrations of leptin and insulin increased during the first 3–6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertensionand tachycardia in the rabbit model of obesity

Leptin links with plasminogen activator inhibitor-1 in human obesity: the SABPA study

The relationship between obesity and the development of cardiovascular disease is well established. However, the underlying mechanisms contributing to vascular disease and increased cardiovascular risk in the obese remain largely unexplored. Since leptin exerts direct vascular effects, we investigated leptin and the relationship thereof with circulating markers of vascular damage, namely plasminogen activator inhibitor–1 antigen (PAI–1ag), von Willebrand factor antigen (vWFag) and urinary albuminto–creatinine ratio (ACR). The study included a bi–ethnic population of 409 African and Caucasian teachers who were stratified into lean (o0.5) and obese (?0.5) groups according to waist–to–height ratio. We obtained ambulatory blood pressure measurements and determined serum leptin levels, PAI–1ag, vWFag and ACR, as markers of vascular damage. The obese group had higher leptin (Po0.001) and PAI–1ag (Po0.001) levels and a tendency existed for higher vWFag (P=0.068). ACR did not differ between the two groups (P=0.21). In single regression analyses positive associations existed between leptin and all markers of vascular damage (all Po0.001) only in the obese group. After adjusting for covariates and confounders in multiple regression analyses, only the association between leptin and PAI–1ag remained (R2=0.440; ?=0.293; P=0.0021). After adjusting for gender, ethnicity and age, additional analyses indicated that leptin also associated with fibrinogen and clot lysis time in both lean and obese groups, which in turn is associated with 24– h blood pressure and pulse pressure. This result provides evidence that elevated circulating leptin may directly contribute to vascular damage, possibly through mechanism related to thrombotic vascular disease