Abstract
Thermogenic adipocytes burn nutrients in order to produce heat. Upon activation, brown adipose tissue (BAT) clears vast amounts of lipids and glucose from the circulation and thus substantially lowers plasma lipid levels. As a consequence, BAT activation protects from the development of atherosclerosis. However, it is unclear if pharmacologic activation of BAT can be exploited therapeutically to reduce plaque burden in established atherosclerotic disease. Here we study the impact of thermogenic adipose tissues on plaque regression in a mouse model of atherosclerosis. Thermogenic adipocytes in atherosclerotic low-density lipoprotein (LDL) receptor (LDLR)-deficient mice were pharmacologically activated by dietary CL316,243 (CL) treatment for 4 weeks and the outcomes on metabolically active tissues, plasma lipids and atherosclerosis were analyzed. While the chronic activation of thermogenic adipocytes reduced adiposity, increased browning of white adipose tissue (WAT), altered liver gene expression, and reduced plasma triglyceride levels, atherosclerotic plaque burden remained unchanged. Our findings suggest that despite improving adiposity and plasma triglycerides, pharmacologic activation of thermogenic adipocytes is not able to reverse atherosclerosis in LDLR-deficient mice.
Highlights
Cardiovascular diseases (CVD) represent a critical threat to human health and account for roughly31.3% of global mortality [1]
HFCS-fed atherosclerotic low-density lipoprotein receptor (LDLR)-deficient mice were switched to chow diet or to chow diet atherosclerotic LDLR-deficient mice were switched to chow diet or to chow diet supplemented with supplemented with CL316,243 (CL) for 4 weeks to pharmacologically activate thermogenic
Food intake was not altered in CL-treated LDLR-deficient mice compared to control mice (Figure 1B) if at all slightly higher as indicated by cumulative food intake over time (Figure 1C)
Summary
Cardiovascular diseases (CVD) represent a critical threat to human health and account for roughly31.3% of global mortality [1]. A promising approach to counteract dyslipidemia and reduce hypercholesterolemia is the activation of thermogenic adipocytes [2,3]. These specialized fat cells utilize high-energy nutrients in order to produce heat and defend the body against cold stress. Nutrients 2019, 11, 463 of norepinephrine from sympathetic nerve terminals and its subsequent binding to adrenergic receptors on adipocytes This physiological activation can be mimicked pharmacologically by treatment with the selective β3 -adrenergic receptor agonist CL316,243 (CL) [4,5]. Intravascular hydrolysis of triglyceride-rich lipoproteins (TRL) results in the release and subsequent utilization of free fatty acids (FFA) by adipocytes as well as enhanced flux of cholesterol-enriched remnant particles to the liver, where they are cleared from the circulation [3]. BAT can be recruited by cold acclimation [17] and enhances energy expenditure [18,19]
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