Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by β3-adrenergic receptor stimulation protects from atherosclerosis in hyperlipidemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism that unlike hyperlipidemic Apoe−/− and Ldlr−/− mice expresses functional apoE and LDLR. BAT activation increases energy expenditure and decreases plasma triglyceride and cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT, subsequently accelerating the hepatic clearance of the cholesterol-enriched remnants. These effects depend on a functional hepatic apoE-LDLR clearance pathway as BAT activation in Apoe−/− and Ldlr−/− mice does not attenuate hypercholesterolaemia and atherosclerosis. We conclude that activation of BAT is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis.

Brown adipose tissue (BAT) is an important player in energy homeostasis due to its ability to combust energy toward heat by virtue of the presence of uncoupling protein 1 (UCP1), a process called nonshivering thermogenesis ( 1 ). The most well-known trigger for activation of BAT is cold, which increases sympathetic outfl ow from the hypothalamic temperature center toward BAT. Here, nerve endings release noradrenalin that binds to adrenergic receptors on the brown adipocyte membrane ( 2 ). Activation of an intracellular signaling cascade subsequently leads to a rapid induction of intracellular lipolysis, mediated by adipose triglyceride lipase (ATGL), hormone sensitive lipase, and monoglyceride lipase, resulting in release of FA from TG-fi lled lipid droplets ( 3 ). FAs are directed to the mitochondria where they either allosterically activate UCP1 present on the inner membrane of the mitochondria or undergo ␤ -oxidation within the mitochondrial matrix ( 2 ). Upon activation, UCP1 dissipates the proton gradient across the inner mitochondrial membrane that is generated by the respiratory chain, resulting in production of heat. Of note, FAs used for activation of UCP1 and ␤ -oxidation appear to be mainly derived from intracellular TG stores, rather than from directly internalized FA, as mice that lack ATGL exhibit defective thermogenesis ( 4 ). Therefore, replenishment of intracellular TG stores within the brown adipocyte is essential for nonshivering thermogenesis in BAT.Replenishment of intracellular TG stores is mediated via three mechanisms: uptake of glucose followed by de novo lipogenesis, uptake of albumin-bound FA, and uptake of triglyceride-rich lipoprotein (TRL)-derived FA from the C-activity, irrespective of particle size, indicating lipolysis-mediated uptake of TG-derived FA rather than whole particle uptake. Cold exposure (7°C) increased the uptake of FA derived from the differently sized particles by BAT, while retaining the selectivity for uptake of FA over cholesteryl ester (CE). At thermoneutrality (28°C), total FA uptake by BAT was attenuated, but the specifi city of uptake of FA over CE was again largely retained. Altogether, we conclude that, in our model, BAT takes up plasma TG preferentially by means of lipolysis-mediated uptake of FA. -Khedoe, P. P. S.

Rationale Primary cilia are cellular protrusions which serve as mechanosensors for fluid flow. In endothelial cells (EC) they function in transducing local blood flow information into functional responses, like nitric oxide production and initiation of gene expression. Cilia are present on EC in areas of low or disturbed flow and absent in areas of high flow. In the embryonic heart high flow regime applies to the endocardial cushion area, and the absence of cilia here coincides with the process of endothelial-to-mesenchymal transition (EndoMT). Objective In this study we investigate the role of the primary cilium in defining the responses of EC to fluid shear stress and in EndoMT. Methods and Results Non-ciliated mouse embryonic EC with a mutation in Tg737/Ift88 were used to compare the response to fluid shear stress to that of ciliated EC. In vitro, non-ciliated EC undergo shear-induced EndoMT which is accompanied by downregulation of Klf4. This Tgfβ/Alk5 dependent transformation is prevented by blocking Tgfβ signaling, overexpression of Klf4, or rescue of the primary cilium. In the hearts of Tg737orpk/orpk embryos Tgfβ/Alk5 signaling was activated in areas in which EC would normally be ciliated, but now lack cilia due to the mutation. In these areas EC show increased Smad2 phosphorylation and expression of αSMA. Conclusions This study demonstrates the central role of primary cilia in rendering EC prone to shear-induced activation of Tgfβ/Alk5 signaling and EndoMT, and thereby provides a functional link between primary cilia and flow related endothelial performance.