Use of fat-fed rats to study the metabolic and vascular sequelae of obesity and beta-adrenergic antagonism

Abstract

Obesity-associated cardiovascular disease exerts profound human and monetary costs, creating a mounting need for cost-effective and relevant in vivo models of the complex metabolic and vascular interrelationships of obesity. Obesity is associated with endothelial dysfunction and inflammation. Free fatty acids (FFA), generated partly through beta-adrenergic receptor-mediated lipolysis, may impair endothelium-dependent vasodilation (EDV) by proinflammatory mechanisms. beta-Adrenergic antagonists protect against cardiovascular events by mechanisms not fully defined. We hypothesized that beta antagonists may exert beneficial effects, in part, by inhibiting lipolysis and reducing FFA. Further, we sought to evaluate the fat-fed rat as an in vivo model of obesity-induced inflammation and EDV. Control and fat-fed rats were given vehicle or beta antagonist for 28 d. Serum FFA were measured to determine the association to serum IL6, TNFalpha, and C-reactive protein and to femoral artery EDV. Compared with controls, fat-fed rats weighed more and had higher FFA, triglyceride, leptin, and insulin levels. Unexpectedly, in control and fat-fed rats, beta antagonism increased FFA, yet inflammatory cytokines were reduced and EDV was preserved. Therefore, reduction of FFA is unlikely to be the mechanism by which beta antagonists protect the endothelium. These results reflect the need for validation of ex vivo models of obesity-induced inflammation and endothelial dysfunction, concurrent with careful control of dietary fat composition and treatment duration.

Figure 1.

Flow data in response to a single injection of acetylcholine (black arrow). Red line represents plateau in flow curve. The area under the flow curve that lies between the acetylcholine injection and the plateau is used to quantitate FTI in milliliters and is outlined in black.

Figure 2.

High-fat feeding resulted in higher serum FFA in vehicle rats (P < 0.05). β-Adrenergic antagonism was associated with increased serum FFA in both control (+, P < 0.01) and fat-fed (*, P < 0.05) rats.

Figure 3.

(A) Serum TNFα. TNFα concentrations were reduced in control rats that received β-adrenergic antagonist treatment. +, P < 0.01. (B) Serum IL6. IL6 concentrations were reduced in control rats that received β-adrenergic antagonist treatment. +, P < 0.01. (C) Serum CRP. β-Adrenergic antagonist treatment reduced CRP in both control and fat-fed rats. #, P < 0.001; *, P < 0.05.

Figure 4.

Femoral artery FTI in response to saline and acetylcholine. (A) Control and (B) fat-fed rats with vehicle pellets are compared with those that received β-adrenergic antagonist pellets. The increase in FTI with β-adrenergic antagonism was not significant (control, P < 0.11; fat-fed, P < 0.17).