Brown adipose tissue takes up plasma triglycerides mostly after lipolysis

Abstract

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.

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

“…12 In fact, we 52 and others 8 have recently shown that FA uptake by activated BAT can reach such extent that BAT activation lowers plasma triglyceride levels. BAT activation through cold exposure largely reduces plasma triglyceride levels in hypertriglyceridemic Apoa5 −/− mice 8 as well as in normolipidemic C57Bl/6J mice, suggesting that BAT activation is a promising target to combat hypertriglyceridemia.…”

“…8,51 Collectively, these data would rather suggest that BAT at least also takes up triglyceride-derived FA via selective delipidation of TRL in a similar manner as heart, skeletal muscle, and WAT. 48,49 Recently, Khedoe et al 52 injected TRL-like particles in coldexposed mice and observed a large increase in the selective Figure 1. Activated brown adipose tissue (BAT) takes up triglyceride (TG)-derived fatty acids after lipolysis.…”

“…Furthermore, glucose is taken up as well via glucose transporter (GLUT) 1 anduptake of radiolabeled triglycerides by BAT, whereas uptake of holoparticles by BAT was only slightly increased. 52 Injection of endogenous VLDL, ex vivo radiolabeled, into mice in which BAT was activated by the selective β3-AR agonist CL316243 also resulted in a selectively increased uptake of triglyceride-derived FA by BAT and predominant uptake of the core remnant by the liver (G. Hoeke, MSc, et al, unpublished data, 2014). These data would indicate that holoparticle uptake by BAT takes place to a low extent and that BAT takes up TRL-derived triglycerides mostly after lipolysis of TRLs.…”

“…Differences in TRL-particle preparation, size, and physiological characteristics (including acquisition of apolipoproteins) may explain the contrasting in vivo kinetics in these studies. 8,52 After uptake of TRL-derived FA by BAT, FA are incorporated into triglycerides and stored in intracellular lipid droplets from where they are released on BAT activation. It can be questioned whether TRL-derived FA can also be directly used for mitochondrial β-oxidation and UCP-1 activation without first being incorporated into the cellular triglyceride pool.…”

Endocrine And Metabolic Adaptations Of Calves To Extra-Uterine Life

“…This requires the action of lipoprotein lipase. This enzyme increases its activity during cold exposure, which presumably refl ects its increased synthesis within brown fat cells and secretion in the capillary lumen [124]. BAT has a considerably higher fatty acid releasing capacity than white fat [122].…”