Brown adipose tissue takes up plasma triglycerides mostly after lipolysis

Abstract

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[(3)H]oleate and [(14)C]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 (3)H-activity by BAT, expressed per gram of tissue, was much higher than the uptake of (14)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 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.

Keywords: cholesterol; chylomicrons; fatty acid metabolism; lipids; lipoprotein lipase; lipoproteins/metabolism.

Fig. 1.

Cold exposure enhances plasma clearance of double-labeled TRL-mimicking particles. [³H]TO- and [¹⁴C]CO-labeled TRL-mimicking particles of different sizes (45, 80, and 150 nm) were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (open symbols) or 7°C (closed symbols) for 24 h prior to the experiment. Blood was collected at the indicated time points, and [³H]TO activity (A–C) as well as [¹⁴C]CO activity (D–F) were measured in plasma. Values are means ± SEM (n = 6). * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the 21°C group.

Fig. 2.

Cold exposure increases uptake of double-labeled TRL-mimicking particles by BAT. [³H]TO- and [¹⁴C]CO-labeled TRL-mimicking particles of different sizes (45, 80, and 150 nm) were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (open symbols) or 7°C (closed symbols) for 24 h prior to the experiment (see Fig. 1). Uptake of [³H]TO-derived activity (A–C) and [¹⁴C]CO activity (D–F) was determined in various organs and expressed as percentage of the injected dose per gram wet tissue weight. Values are means ± SEM (n = 6). * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the 21°C group. gWAT, gonadal WAT; sWAT, subcutaneous WAT.

Fig. 3.

Lipolysis index in muscle, WAT, and BAT points to selective FA uptake at 21°C and 7°C. [³H]TO- and [¹⁴C]CO-labeled TRL-mimicking particles of different sizes (45, 80, and 150 nm) were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (open symbols) or 7°C (closed symbols) for 24 h prior to the experiment (see Fig. 1). From the uptake of [³H]TO-derived activity and [¹⁴C]CO activity by the various organs (see Fig. 2), the lipolysis index was calculated as the ratio of ³H-activity (%/g) and ¹⁴C-activity (%/g) for particles of 45 nm (A), 80 nm (B), and 150 nm (C). Values are means ± SEM (n = 6). * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the 21°C group.

Fig. 4.

Retention of core remnants within BAT is at least partly due to uptake by BAT. [³H]COE-labeled TRL-mimicking particles of 150 nm were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (A) or 7°C (B) for 24 h. Uptake of [³H]COE-derived activity was determined after 15, 60, and 300 min in various organs, and expressed as percentage of the injected dose per gram wet tissue weight. Values are means ± SEM (n = 6).

Fig. 5.

Thermoneutrality attenuates plasma clearance of double-labeled TRL-mimicking particles. [³H]TO- and [¹⁴C]CO-labeled TRL-mimicking particles of different size (45, 80, and 150 nm) were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (open symbols) or 28°C (closed symbols) for 4 h prior to the experiment. Blood was collected at the indicated time points, and [³H]TO activity (A–C) and [¹⁴C]CO activity (D–F) were measured in plasma. Values are means ± SEM (n = 6). * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the 21°C group.

Fig. 6.

Thermoneutrality attenuates uptake of double-labeled TRL-mimicking particles by BAT. [³H]TO- and [¹⁴C]CO-labeled TRL-mimicking particles of different size (45, 80, and 150 nm) were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (open symbols) or 28°C (closed symbols) for 4 h prior to the experiment (see Fig. 5). Uptake of [³H]TO- (A–C) and [¹⁴C]CO-derived radioactivity (D–F) was determined in various organs, and expressed as percentage of the injected dose per gram wet tissue weight (D–F). Values are means ± SEM (n = 6). * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the 21°C group.

Fig. 7.

Lipolysis index in muscle, WAT, and BAT points to selective FA uptake at thermoneutrality. [³H]TO- and [¹⁴C]CO-labeled TRL-mimicking particles of different sizes (45, 80, and 150 nm) were injected intravenously into 4 h fasted mice that had been exposed to an ambient temperature of 21°C (open symbols) or 28°C (closed symbols) for 4 h prior to the experiment (see Fig. 5). From the uptake of [³H]TO- and [¹⁴C]CO-derived radioactivity in the various organs (see Fig. 6), the lipolysis index was calculated as the ratio of ³H-activity (%/g) and ¹⁴C-activity (%/g) for particles of 45 nm (A), 80 nm (B), and 150 nm (C). Values are means ± SEM (n = 6). * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the 21°C group.