Abstract 68: Activation of Brown Adipose Tissue Reduces Development of Atherosclerosis
Objectives: Brown adipose tissue (BAT) recently emerged as a novel player in lipoprotein metabolism. BAT combusts high amounts fatty acids into heat resulting in reduced plasma triglyceride (TG) levels as well as obesity. However, the precise role of BAT in cholesterol metabolism and atherosclerosis development remains unclear. We aimed to assess the effect of stimulating BAT activity by ß3-adrenergic receptor (ß3-AR) agonism on lipoprotein metabolism and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism.
Methods and results: Mice were fed a Western-type diet to induce dyslipidemia and were treated subcutaneously with the selective ß3-AR agonist CL316243 (3x20 μg/week) or vehicle for 10 weeks. ß3-AR agonism reduced total fat mass (-59%) and white adipose tissue (WAT) pad size (-40%). ß3-AR agonism decreased the size of intracellular lipid vacuoles in BAT, and increased UCP-1 expression in WAT, indicating activation of brown adipocytes (i.e. BAT) as well as their precursors (i.e. WAT). These effects were accompanied by increased uptake of glycerol tri[3H]oleate from VLDL-like particles by BAT (+125%) and by WAT (+120%) as well as fatty acid oxidation (+25%) as determined by indirect calorimetry. In line with these data, activation of BAT decreased plasma levels of TG (-46%) and (V)LDL-cholesterol (-24%) and increased HDL-cholesterol (+23%), accompanied by increased reverse cholesterol transport (+2.5-fold). As a consequence of improving lipoprotein metabolism, BAT activation reduced atherosclerosis development (-43%) as well as lesion severity, indicated by more mild type I-III lesions (+64%) and reduced severe type IV-V lesions (-66%), in the aortic root. These effects were dependent on a functional hepatic apoE-LDLr clearance pathway, as BAT activation in apoe-/- and ldlr-/- mice lowered plasma TG levels but did not attenuate hypercholesterolemia and atherosclerosis
Conclusion: We demonstrate that activation of BAT via the ß3-AR is a powerful tool to reduce dyslipidemia and protect against atherosclerosis. These findings indicate that activation of BAT is a promising novel strategy to combat dyslipidemia and cardiovascular disease.
Author Disclosures: J. Berbée: None. M.R. Boon: None. P.P.S. Khedoe: None. A. Bartelt: None. S. Kooijman: None. N. Vazirpanah: None. L.P.J. Brouwers: None. P.L.S. Gordts: None. J.D. Esko: None. P.S. Hiemstra: None. L.M. Havekes: None. J. Heeren: None. P.C.N. Rensen: None.
- © 2014 by American Heart Association, Inc.