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Introduction: Brown adipose tissue (BAT) produces heat by burning triglyceride (TG)-derived fatty acids. As a result, BAT accelerates the formation and hepatic clearance of cholesterol-enriched lipoprotein remnants via the apoE-LDL receptor (LDLR) pathway, thereby alleviating hypercholesterolemia. Since statins upregulate hepatic LDLR expression, the aim of this study was to investigate whether BAT activation and statin treatment cooperate in lowering hyperlipidemia and atherosclerosis. Methods and Results: APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the selective β3-AR agonist CL316243 that activates BAT (CL, 20 μg/day; s.c.), atorvastatin (statin, 0.0036% w/w, in diet) or both. BAT activation alone and combined with statin treatment increased energy expenditure (+15%) as a result of increased fat oxidation (+50%). Furthermore, BAT activation decreased the lipid droplet content within BAT (-50%) and induced browning of subcutaneous white adipose tissue. BAT activation alone and combined with statin treatment also lowered plasma TG levels (-60%). In addition, plasma cholesterol was lowered by both BAT activation (-29%) and statin (-31%), but even further by the combination (-44%). The uptake of TG-derived fatty acids from glycerol tri[3H]oleate and [14C]cholesteryl oleate-labeled VLDL-mimicking particles into BAT was enhanced by BAT activation (+234%) and on top of statin (+220%), but not by statin alone. The hepatic uptake of the cholesterol-enriched remnants tended to be increased by BAT activation (+18%) or statin (+22%), and was markedly increased by the combination of BAT activation and statin treatment (+70%). Hepatic cholesterol levels were reduced by statin alone and the combination (-41%). Importantly, atherosclerosis development was decreased by BAT activation (-42%) and statin (-50%) alone and further decreased by the combination (-70%). Conclusions: BAT activation enhances the lipid-lowering and anti-atherogenic effect of statin treatment. We postulate that combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular diseases.

Objectives: The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintained weight loss and reduction of dyslipidemia in experimental and human obesity. Brown adipose tissue (BAT) that burns lipids towards heat using UCP1, recently emerged as a major player in lipoprotein metabolism and is present and active in human adults. The aim of the present study was to elucidate the mechanism by which CB1R blockade reverses dyslipidemia and obesity, with special focus on BAT. Methods and results: Diet-induced obese APOE*3-Leiden.CETP transgenic mice, a well-established model for human-like lipoprotein metabolism, were treated with the systemic CB1R blocker rimonabant (10 mg/kg/day) for 4 weeks. Rimonabant persistently decreased body weight (-25%, pin vitro blockade of the CB1R in cultured brown adipocytes resulted in 2.5-fold upregulation of UCP1. Importantly, the in vivo results could be fully recapitulated using the strictly peripheral CB1R antagonist AM6545 (10 mg/kg/day) that does not induce hypophagia. Conclusion: CB1R blockade reduces dyslipidemia and obesity by peripheral activation of BAT. Selective targeting of peripheral CB1R in BAT has thus great therapeutic potential in decreasing dyslipidemia and obesity and ultimately cardiovascular diseases.

Objectives: SNPs near the melanocortin 4 receptor (MC4R) gene are associated with cardiovascular diseases (CVD) and deficiency of MC4R is the most common monogenic cause of obesity, a major risk factor for the development of CVD. MC4R-deficient individuals not only show increased food intake but also lower basal energy expenditure. Furthermore, pharmacological inhibition of the central MC4R signaling by SHU9119 in mice increases weight gain independent of food intake. Since brown adipose tissue (BAT) importantly contributes to energy expenditure by combusting high amounts of triglycerides (TG) into heat, the aim of the study was to evaluate the effect of inhibiting MCR4 on VLDL-metabolism and BAT activity in mice. Methods and results: Female APOE*3-Leiden.CETP transgenic mice were fed a cholesterol-enriched Western-type diet for 4 weeks, matched on body weight and plasma lipids, and infused with either SHU9119 or vehicle for 2 weeks via an osmotic mini-pump into the lateral ventricle while being fed the same diet. SHU9119 increased body fat (+50%) and decreased fat oxidation (-42%). Shu9119 increased plasma VLDL-TG levels (+30%). Whereas hepatic VLDL-TG production rate was not affected, Shu9119 severely impaired clearance of VLDL-TG, explained by reduced uptake of [ 3 H]TG by BAT (-25%). In BAT, SHU9119 decreased UCP-1 protein (-60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Since SHU9119 increased food intake (+30%), SHU9119 was also administered in mice that were pair-fed with the vehicle-treated group. Under these conditions, SHU9119 still exhibited these effects, indicating MC4R inhibition impairs BAT activity independent of food intake. Conclusion: Inhibition of central MC4R signaling by SHU9119 increases VLDL-TG levels and decreases energy expenditure specifically by impairing BAT function. We anticipate that MC4R regulates adiposity and VLDL metabolism not only by regulating food intake, but also by modulating BAT activity, and that activation of MC4R is a promising strategy to combat obesity and CVD by increasing BAT activity.

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[ 3 H]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.