Cold acclimation recruits human brown fat and increases nonshivering thermogenesis

Abstract

In recent years, it has been shown that humans have active brown adipose tissue (BAT) depots, raising the question of whether activation and recruitment of BAT can be a target to counterbalance the current obesity pandemic. Here, we show that a 10-day cold acclimation protocol in humans increases BAT activity in parallel with an increase in nonshivering thermogenesis (NST). No sex differences in BAT presence and activity were found either before or after cold acclimation. Respiration measurements in permeabilized fibers and isolated mitochondria revealed no significant contribution of skeletal muscle mitochondrial uncoupling to the increased NST. Based on cell-specific markers and on uncoupling protein-1 (characteristic of both BAT and beige/brite cells), this study did not show "browning" of abdominal subcutaneous white adipose tissue upon cold acclimation. The observed physiological acclimation is in line with the subjective changes in temperature sensation; upon cold acclimation, the subjects judged the environment warmer, felt more comfortable in the cold, and reported less shivering. The combined results suggest that a variable indoor environment with frequent cold exposures might be an acceptable and economic manner to increase energy expenditure and may contribute to counteracting the current obesity epidemic.

Figures

Figure 1. Individual data of BAT activity and NST before and after cold acclimation.

Detectable BAT volume and NST increased significantly upon the cold acclimation period. A significant relation is found between NST and BAT activity. (A) Individual data on BAT activity. Left panel: detectable BAT volume (cc); middle panel: glucose uptake rate (μmol/min/100 g); right panel: NST (%). Please note that detectable BAT volume is an overestimation of true active BAT volume. (B) Relation between NST and BAT. Left panel: NST expressed as percentage and BAT activity as SUV mean; right panel: NST expressed as percentage and BAT activity as SUV max. (C) [18F]FDG-PET images of the upper body after cold exposure in a female (top) and a male subject (bottom), before (pre) and after (post) cold acclimation. Main BAT locations are indicated with black arrows; additionally, paravertebral BAT is activated. (D) Transversal CT (top) and PET/CT fusion (bottom) slice of the supraclavicular region demonstrating [18F]FDG-uptake in BAT locations (white arrows) after cold exposure, both before and after the cold acclimation period.

Figure 2. No effect of cold acclimation on SM respiration.

(A) Mitochondrial density (n = 16). Panels B–E represent the data from permeabilized muscle fibers (n = 16, 8 male/8 female) corrected for mitochondrial density, while G and H (n = 11, 5 male/6 female) and F–J (n = 9, 3 male/6 female) reflect the data from isolated mitochondria obtained in a subset of subjects. (B) Oxygen consumption not linked to ATP synthesis (state 4). (C) Oxygen consumption upon substrates only (malate, malate + octanoylcarnitine, malate + glutamate; state 2). (D) ADP-stimulated respiration (state 3) fuelled by various complex I– and complex II–linked substrates. (E) Maximally uncoupled respiration upon the chemical uncoupler FCCP. (F) Mitochondrial oxygen consumption not linked to ATP synthesis (state 4) on pyruvate and palmitoyl-CoA + carnitine. (G) Mean EC50 value of palmitate concentration-response curves. (H) Mean Vmax of palmitate concentration-response curves. (I) ADP-stimulated respiration (state 3). (J) Maximally uncoupled respiration upon FCCP fueled by pyruvate or palmitoyol-CoA + carnitine. The effects of cold acclimation on all SM parameters were tested with paired-samples t tests. Black and white bars represent the values before and after cold acclimation, respectively. Values are expressed as means with SEM. M, malate; G, glutamate; S, succinate; O, octanoyl-carnitine.

Figure 3. Graphical reflection of VAS scales.

A higher sensation and thermal comfort and lower self-reported shivering were reported on day 10 as compared with day 3. The iAUC decreased with 57%, 72%, and 61% for sensation, thermal comfort, and self-reported shivering respectively (P < 0.05; P < 0.01; P < 0.01, respectively). This was tested with a paired-samples t test. Values are expressed as means with SEM. Black squares represent the third day of acclimation (first time 6 hours cold exposure); white squares represent the tenth day.