PuSH - Publication Server of Helmholtz Zentrum München: Mirabegron-induced brown fat activation does not exacerbate atherosclerosis in mice with a functional hepatic ApoE-LDLR pathway.

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Ying, Z.* ; van Eenige, R.* ; Beerepoot, R.* ; Boon, M.R.* ; Kloosterhuis, N.J.* ; Van De Sluis, B.* ; Bartelt, A. ; Rensen, P.C.N.* ; Kooijman, S.*

Mirabegron-induced brown fat activation does not exacerbate atherosclerosis in mice with a functional hepatic ApoE-LDLR pathway.

Pharmacol. Res. 187:106634 (2023)

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Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used β3-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)- and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipoprotein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Atherosclerosis ; Brown Adipose Tissue ; Lipolysis ; Lipoproteins ; Vldl Secretion ; White Adipose Tissue; Adipose-tissue; Aggravates Atherosclerosis; Lipoprotein; Metabolism; Agonist

ISSN (print) / ISBN 1043-6618

e-ISSN 1096-1186

Journal Pharmacological Research

Quellenangaben Volume: 187, Article Number: 106634

Publisher Elsevier

Publishing Place 24-28 Oval Rd, London Nw1 7dx, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants China Scholarship Council
Hartstichting
Deutsche Forschungsgemeinschaft