Geerte Hoeke

Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

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 takes up plasma triglycerides mostly after lipolysis

Brown adipose tissue (BAT) produces heat by burning TGs that are stored within intracellular lipid droplets and need to be replenished by the uptake of TG-derived FA from plasma. It is currently unclear whether BAT takes up FA via uptake of TG-rich lipoproteins (TRLs), after lipolysis-mediated liberation of FA, or via a combination of both. Therefore, we generated glycerol tri[3H]oleate and [14C]cholesteryl oleate double-labeled TRL-mimicking particles with an average diameter of 45, 80, and 150 nm (representing small VLDL to chylomicrons) and injected these intravenously into male C57Bl/6J mice. At room temperature (21°C), the uptake of 3H-activity by BAT, expressed per gram of tissue, was much higher than the uptake of 14C-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 specificity 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.

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

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 lipase-mediated 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 apoE-low-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.

Relevance of lipid metabolism for brown fat visualization and quantification.

Purpose of review Brown adipose tissue (BAT) is an emerging target to combat cardiometabolic disorders as it can take up substantial amounts of glucose and lipids from the circulation for heat production. This review focuses on new concepts in BAT physiology and discusses the need for new techniques to determine BAT activity in humans. Recent findings Mouse studies showed that BAT activation selectively increases oxidation of lipids over glucose, by recruiting fatty acids from intracellular triglycerides. To replenish these intracellular lipid stores, brown adipocytes take up both glucose and triglyceride-derived fatty acids, resulting in attenuation of dyslipidaemia, insulin resistance and atherosclerosis. Clinical studies identified the involvement of the &bgr;3-adrenergic receptor in BAT activation and demonstrated that human BAT activation also selectively increases lipid oxidation. Notably, insulin resistance during ageing or weight gain reduces the capacity of BAT to internalize glucose, without reducing fatty acid uptake or oxidative metabolism. Summary Preclinical studies established BAT as an important target to combat cardiometabolic disorders and elucidated underlying mechanisms whereas clinical studies identified therapeutic handles. Development of novel lipid-based PET-CT tracers and identification of translational biomarkers of BAT activity are required as alternatives to [18F]fluorodeoxyglucose PET-CT to accelerate clinical development of BAT-activating therapeutic strategies.

The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG‐891 acutely induced O2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. TUG‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG‐891 is a promising strategy to increase lipid combustion and reduce obesity.

The Effects of Selective Hematopoietic Expression of Human IL-37 on Systemic Inflammation and Atherosclerosis in LDLr-Deficient Mice

The human cytokine interleukin (IL)-37 has potent anti-inflammatory capacities, and hematopoietic cell-specific transgenic overexpression of IL-37 in mice protects against septic shock and colitis. In the present study we investigated the effect of hematopoietic expression of IL-37 on atherosclerosis development under low-grade inflammatory conditions. Low-density lipoprotein receptor (LDLr)-deficient mice were lethally irradiated and transplanted with bone marrow from IL-37-transgenic or control wild-type mice and fed a Western-type diet (WTD; 1% cholesterol) for eight weeks. Metabolic and inflammatory parameters were monitored and atherosclerosis was assessed in the aortic valve area. Hematopoietic IL-37 expression did not influence body weight, food intake and plasma cholesterol levels during the study. Plasma soluble E-selectin levels were increased with WTD-feeding as compared to chow-feeding, but were not influenced by IL-37 expression. IL-37 expression reduced the inflammatory state as indicated by reduced white blood cell counts and by reduced basal and lipopolysaccharide-induced cytokine response by peritoneal macrophages ex vivo. IL-37 expression did not influence the atherosclerotic lesion area. Lesion composition was marginally affected. Smooth muscle cell content was decreased, but macrophage and collagen content were not different. We conclude that under low-grade inflammatory conditions, hematopoietic IL-37 expression reduces the inflammatory state, but does not influence atherosclerosis development in hyperlipidemic LDLr-deficient mice.