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.

Highlights d A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis d Human brown adipocytes lack b 3 -AR and do not respond to mirabegron in vitro d Norepinephrine-induced respiration is driven by b 2 -AR, which co-localizes with UCP1 d b 2 -AR is the main target for pharmacological activation of human brown adipocytes

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.

Atherosclerosis, for which hyperlipidemia is a major risk factor, is the leading cause of morbidity and mortality in Western society, and new therapeutic strategies are highly warranted. Brown adipose tissue (BAT) is metabolically active in human adults. Although positron emission tomography-computed tomography using a glucose tracer is the golden standard to visualize and quantify the volume and activity of BAT, it has become clear that activated BAT combusts fatty acids rather than glucose. Here, we review the role of brown and beige adipocytes in lipoprotein metabolism and atherosclerosis, with evidence derived from both animal and human studies. On the basis of mainly data from animal models, we propose a model in which activated brown adipocytes use their intracellular triglyceride stores to generate fatty acids for combustion. BAT rapidly replenishes these stores by internalizing primarily lipoprotein triglyceride-derived fatty acids, generated by lipoprotein lipasemediated hydrolysis of triglycerides, rather than by holoparticle uptake. As a consequence, BAT activation leads to the generation of lipoprotein remnants that are subsequently cleared via the liver provided that an intact apoElow-density lipoprotein receptor pathway is present. Through these mechanisms, BAT activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. Initial studies suggest that BAT activation in humans may also reduce triglyceride and cholesterol levels, but potential antiatherogenic effects should be assessed in future studies. (Circ Res. 2016;118:173-182.

Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500).