Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans
Article Figures & Tables
Figures
- Figure 1
Temperature-dependent BAT acclimation. A–D: Representative PET/CT fused images of the cervical-supraclavicular region (left panels: coronal view; right panels: transverse view) of one subject during monthly temperature acclimation. BAT (HU: −300 to −10 and SUV ≥2) is shown in red. Baseline BAT volume and mean SUV and activity were 26 mL and 2.65 and 0.238 MBq, respectively (A). All BAT parameters increased after 1 month of mild cold acclimation (19°C) (B), decreased to nearly baseline level after the thermoneutral month (24°C) (C), and BAT was nearly completely muted at the end of the 1-month mild warm exposure in the final month (27°C) (D). Mean fold changes (N = 5) of BAT volume (E) and mean SUV (F) and BAT activity (G), relative to month 1 (24°C), were significant across 4-month acclimation. Whole fat activity, as defined by 18F-fluodeoxyglucose uptake within tissue of fat density (HU: −300 to −10), followed the same pattern (H) and interacted significantly with temperature acclimation. Room (I) and individual exposed temperatures (J), but not environmental seasonal fluctuations (I), tracked BAT and whole fat metabolic changes in the predicted temperature-dependent manner. Correlative analysis between BAT parameters and temperature exposure is shown in Supplementary Table 1. Individual PET/CT images and temperature profiles are shown in Supplementary Figs. 4–7. *P < 0.05 compared with month 1 (24°C); #P < 0.05 compared with month 2 (19°C).
- Figure 2
Metabolic consequences of BAT acclimation at 19°C. A and B: Comparison of postprandial glucose and insulin excursions after a mixed meal at 1300 h before and after cold acclimation, respectively, measured at 19°C. Glucose excursions were unchanged but insulin levels decreased, with a significant reduction in AUC, after mild cold acclimation (month 2). Accordingly, adipocyte insulin resistance (IR) was the lowest (C) and Matsuda index (an indicator of insulin sensitivity) was the highest (D) after cold acclimation (month 2). These changes in glucose metabolism were accompanied by an increase in circulating adiponectin (E) and a decrease in circulating leptin (F). Cold acclimation–induced changes (months 1 and 2) in circulating adiponectin (G) and leptin levels (H) correlated negatively with changes in BAT activity. Adiponectin and leptin mRNA displayed concordant changes in subcutaneous adipose tissue biopsies with circulating levels, and changes in GLUT4 tracked those of adiponectin (I). aP < 0.05 compared with month 1 (24°C), bP < 0.05 compared with month 2 (19°C), cP < 0.05 compared with month 3 (24°C), and dP < 0.05 compared with month 4 (27°C).
- Figure 3
Metabolic consequences of BAT acclimatization at 24°C. A and B: Comparison of postprandial glucose and insulin excursions after a mixed meal at 1300 h before and after cold acclimatization, respectively, measured at 24°C. Unlike measurements at 19°C (Fig. 2A and B), no significant changes were observed in glucose or insulin excursions. Accordingly, adipocyte insulin resistance (IR) (C) and Matsuda index (an indicator of insulin sensitivity) (D) were unchanged. Circulating adiponectin increased (E), while leptin decreased (F), identical to measurements observed at 19°C (Fig. 2E and F). Cold acclimatization–induced changes (months 1 and 2) in circulating adiponectin (G) and leptin levels (H) correlated negatively with changes in BAT activity. In contrast to that observed in adipose tissue (Fig. 2I), adiponectin and GLUT4 mRNA did not change significantly in muscle (I). cP < 0.05 compared with month 3 (24°C); dP < 0.05 compared with month 4 (27°C).
- Figure 4
BAT and beige fat gene changes in adipose tissue biopsies across 4-month acclimatization. A: Changes in general BAT gene expression (general BAT genes are defined as genes ascribed to general BAT function and do not indicate their developmental origin). Expression of CIDEA, but not others, changed significantly (P = 0.04) during acclimatization across 4-month period. B: Changes in classic BAT gene expression. Classic BAT genes are defined as those expressed in interscapular BAT in animals or human infants (50). C: Changes in beige fat gene expression. Beige fat genes are defined as those expressed in inducible brown adipocytes, also known as brite or beige adipocytes, found within WAT depots. No significant changes were observed in classic BAT or beige fat genes across temperature acclimation.
Tables
- Table 1
PET/CT parameters across 4 months of acclimation
Month 1: 24°C Month 2: 19°C Month 3: 24°C Month 4: 27°C Ptrend BAT volume (mL) 55 ± 61 78 ± 84a 63 ± 81 58 ± 81 0.036 BAT mean SUV 3.2 ± 0.8 3.8 ± 1.3 3.4 ± 1.0 3.4 ± 0.8 0.35 BAT activity (MBq) 0.65 ± 0.76 1.0 ± 1.3a 0.8 ± 1.1 0.7 ± 1.0 0.038 BAT radiodensity (HU) −58.8 ± 7.2 −44.2 ± 6.8 −55.4 ± 6.5 −69.2 ± 6.8 <0.01 Whole fat mean SUV 0.61 ± 0.13 0.68 ± 0.18a 0.63 ± 0.17 0.59 ± 0.16 0.035 Muscle mean SUV 0.46 ± 0.08 0.41 ± 0.04 0.43 ± 0.05 0.48 ± 0.08 0.52 Liver mean SUV 1.68 ± 0.08 1.50 ± 0.14 1.61 ± 0.15 1.67 ± 0.16 0.15 Data are means ± SD. At the end of each testing month, subjects underwent acute thermometabolic evaluation at either 24°C or 19°C.
aP < 0.05 (month 1 vs. 2).
- Table 2
Physiologic parameters across 4 months of acclimation
Month 1: 24°C Month 2: 19°C Month 3: 24°C Month 4: 27°C Ptrend 24°C 19°C 24°C 19°C 24°C 19°C 24°C 19°C 24°C 19°C Total EE (kcal) 2,472 ± 180 2,624 ± 198a 2,366 ± 358 2,543 ± 410a 2,400 ± 252 2,555 ± 346a 2,341 ± 255 2,505 ± 322a 0.45 0.46 Respiratory quotient 0.84 ± 0.03 0.84 ± 0.01 0.84 ± 0.02 0.83 ± 0.02 0.85 ± 0.02 0.84 ± 0.02 0.84 ± 0.03 0.85 ± 0.02 0.72 0.47 Total activity (units) 8.4 ± 1.6 8.4 ± 2.8 7.6 ± 2.9 7.1 ± 2.4 6.8 ± 3.7 7.1 ± 4.1 7.9 ± 5.0 7.2 ± 4.7 0.54 0.38 Surface electromyography (×10−6 RMS) 2.8 ± 0.4 2.5 ± 1.3 2.7 ± 0.3 2.6 ± 0.2 2.8 ± 0.5 2.7 ± 0.2 2.8 ± 0.3 2.6 ± 0.4 0.98 0.83 CIT (%) 6.2 ± 4.1 7.4 ± 3.1 6.2 ± 3.9 6.8 ± 3.2 0.16 DIT (%) 10.3 ± 13.1 33.4 ± 18.2 19.0 ± 15.4 42.2 ± 17.4a,b 19.1 ± 16.0 37.1 ± 19.6a 22.5 ± 11.0 34.4 ± 19.2a 0.30 0.36 Data are means ± SD. At the end of each testing month, subjects underwent acute thermometabolic evaluation at either 24°C or 19°C. RMS, root mean square.
aP < 0.05 compared with 24°C during acute thermometabolic evaluation each month;
bP < 0.05 (month 1 vs. 2) compared with matching measurement at same temperature performed at respective months as indicated.
- Table 3
Nutritional and body compositional parameters across 4 months of acclimation
Month 1: 24°C Month 2: 19°C Month 3: 24°C Month 4: 27°C Ptrend Dietary intake Caloric (kcal/day) 2,530 ± 321 2,620 ± 412 2,623 ± 342 2,514 ± 359 0.32 Protein (g/day) 126 ± 16 131 ± 19 131 ± 15 127 ± 18 0.35 Fat (g/day) 88 ± 9 91 ± 13 93 ± 11 86 ± 10 0.16 Carbohydrate (g/day) 319 ± 42 331 ± 51 329 ± 44 320 ± 48 0.44 Appetite/hunger VAS Hunger AUC 13.1 ± 6.3 20.7 ± 7.0 17.5 ± 6.1 15.5 ± 3.5 0.13 Satiety AUC 35.8 ± 4.6 25.7 ± 8.5 25.5 ± 5.4 27.9 ± 7.9 0.09 Desire to eat AUC 14.6 ± 4.3 20.1 ± 3.4a,b 17.9 ± 4.2 16.5 ± 5.3 0.003 Body composition Body weight (kg) 74.4 ± 7.3 74.8 ± 7.5 74.9 ± 7.4 74.7 ± 7.7 0.72 Lean mass (kg) 55.8 ± 6.0 56.3 ± 6.1 56.6 ± 6.3 56.1 ± 6.4 0.56 Fat mass (kg) 14.6 ± 0.5 14.5 ± 0.8 14.6 ± 1.4 14.7 ± 1.7 0.95 % body fat 20.92 ± 2.00 20.62 ± 1.64 20.64 ± 2.22 20.88 ± 2.51 0.99 Data are means ± SD. At the end of each testing month, subjects underwent acute thermometabolic evaluation at either 24°C or 19°C.
aP < 0.05 (month 1 vs. 2),
bP < 0.05 (months 2 vs. 4) compared with matching measurement at same temperature performed at respective months as indicated.
- Table 4
Hormonal and metabolic parameters across 4 months of acclimation
Month 1: 24°C Month 2: 19°C Month 3: 24°C Month 4: 27°C Ptrend 24°C 19°C 24°C 19°C 24°C 19°C 24°C 19°C 24°C 19°C Sympathoadrenal Urinary epinephrine (μg/day) 7.5 ± 5.0 8.0 ± 4.8 7.5 ± 3.9 8.3 ± 5.6 7.5 ± 4.4 7.7 ± 4.6 8.3 ± 6.1 7.7 ± 5.1 0.97 0.94 Urinary norepinephrine (μg/day) 46 ± 29 53 ± 14 56 ± 30 64 ± 20 35 ± 9 61 ± 18a 37 ± 5 58 ± 24 0.42 0.56 Glucocorticoid axis ACTH AUC (pg ⋅ min/mL) 207 ± 61 199 ± 73 199 ± 51 197 ± 65 203 ± 74 176 ± 61 209 ± 71 199 ± 83 0.20 0.40 Cortisol AUC (μg ⋅ min/mL) 0.96 ± 0.14 0.91 ± 0.13 0.87 ± 0.10 0.95 ± 0.12 0.81 ± 0.13 0.84 ± 0.17 0.90 ± 0.15 0.88 ± 0.22 0.14 0.39 Urinary cortisol (μg/day) 49 ± 9 36 ± 13 49 ± 27 39 ± 9 39 ± 11 38 ± 11 39 ± 22 49 ± 21 0.42 0.25 Thyroid axis TSH AUC (μIU ⋅ min/mL) 7.8 ± 3.5 8.0 ± 2.8 7.5 ± 3.6 7.3 ± 2.1 8.6 ± 4.3 7.3 ± 2.2 8.8 ± 3.5c 7.6 ± 1.9 0.38 0.39 Free T4 AUC (pg ⋅ min/mL) 95 ± 13 95 ± 9 93 ± 12 92 ± 12 93 ± 9 93 ± 11 90 ± 9 94 ± 9 0.39 0.54 Free T3 AUC (pg ⋅ min/mL) 26 ± 1 27 ± 1 29 ± 2b 28 ± 1 28 ± 3 27 ± 2 26 ± 2d 28 ± 2 0.16 0.59 Free T3/free T4 AUC 2,381 ± 490 2,410 ± 345 2,642 ± 574b 2,556 ± 393 2,513 ± 449 2,511 ± 466 2,515 ± 481 2,491 ± 403 0.06 0.41 Glucose and lipid metabolism Total glucose AUC (mg ⋅ min/mL) 7.38 ± 0.64 7.32 ± 0.37 7.22 ± 0.51 7.25 ± 0.63 7.22 ± 0.73 7.32 ± 0.63 7.14 ± 0.51 7.11 ± 0.74 0.75 0.71 Postprandial glucose AUC (mg ⋅ min/mL) 2.73 ± 0.27 2.68 ± 0.34 2.59 ± 0.13 2.68 ± 0.29 2.64 ± 0.40 2.57 ± 0.29 2.64 ± 0.15 2.53 ± 0.27 0.79 0.63 Total insulin AUC (IU ⋅ min/L) 170 ± 102 210 ± 83 198 ± 97 143 ± 49 212 ± 118 186 ± 123 171 ± 87 182 ± 128 0.08 0.44 Postprandial insulin AUC (IU ⋅ min/L) 106 ± 64 133 ± 57 111 ± 52 77 ± 22 132 ± 85 114 ± 80 103 ± 55 109 ± 79 0.19 0.31 Total free fatty acid AUC (mEq ⋅ min/L) 3.53 ± 0.70 3.76 ± 1.05 3.36 ± 0.31 3.37 ± 1.16 2.73 ± 0.86 3.20 ± 0.40 3.65 ± 1.09 3.76 ± 0.41 0.36 0.68 Fasting total cholesterol (mg/dL) 120 ± 24 132 ± 24 117 ± 16 136 ± 11 0.13 Fasting LDL (mg/dL) 71 ± 21 75 ± 21 62 ± 13 76 ± 10 0.20 Fasting TG (mg/dL) 57 ± 16 68 ± 27 68 ± 15 65 ± 22 0.31 Fasting HDL (mg/dL) 38 ± 7 44 ± 7 41 ± 7 46 ± 4d 0.03 Adipokine Leptin AUC (ng ⋅ min/mL) 16 ± 5 15 ± 6 14 ± 3b 12 ± 2a,b 29 ± 15 26 ± 11 25 ± 12 25 ± 11c 0.01 0.002 Adiponectin AUC (pg ⋅ min/mL) 99 ± 38 103 ± 37 117 ± 51b 127 ± 49a,b 78 ± 31 77 ± 32 74 ± 32c 82 ± 38c 0.0007 0.0003 FGF21 AUC (pg ⋅ min/mL) 333 ± 57 411 ± 104 343 ± 46 460 ± 91a,b 350 ± 25 400 ± 80 370 ± 37 435 ± 75 0.28 0.10 Data are means ± SD. At the end of each testing month, subjects underwent acute thermometabolic evaluation at either 24°C or 19°C. ACTH, adrenocortotropic hormone.
aP < 0.05 compared with 24°C during acute thermometabolic evaluation each month;
bP < 0.05 (month 1 vs. 2),
cP < 0.05 (months 2 vs. 4), and
dP < 0.05 (months 1 vs. 4) compared with matching measurement at the same temperature performed at respective months as indicated.
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