Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans

Abstract

In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24 °C [month 1] → 19 °C [month 2] → 24 °C [month 3] → 27 °C [month 4]) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits.

Trial registration: ClinicalTrials.gov NCT01730105.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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.