Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men

Abstract

Key points: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized.

Abstract: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13)C]-palmitate and [3-(3)H]-glucose tracer methodologies coupled with positron emission tomography using (11)C-acetate and (18)F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1), respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WAT lipolysis is closely associated with BAT metabolic activation upon acute cold exposure in healthy men. In humans, muscle glucose utilization during shivering contributes to a much greater extent than BAT to systemic glucose utilization during acute cold exposure.

Figure 1. BAT energy metabolism during acute cold exposure

BAT monoexponential decay slope from peak ¹¹C activity (BAT oxidative index, A), BAT radio density at room temperature and during cold exposure (B), BAT volume of activity during cold exposure (C), total BAT oxidative index at room temperature and during cold exposure (D), and fractional (E) and net glucose uptake in cervicothoracic tissues (F). G and H, the relationship between BAT glucose partitioning and fractional and net glucose uptake in BAT. Values presented as mean ± SEM (n = 12). Different from room temperature at *P ≤ 0.01, **P ≤ 0.001. Different from BAT at ^#P < 0.05.

Figure 2. BAT glucose metabolism during cold exposure

A and B, Spearman correlation between BAT radio density prior to intravenous (i.v.) injection of ¹⁸FDG and fractional (A) and net (B) BAT glucose uptake. C and D, Spearman correlation between BAT monoexponential decay slope from peak ¹¹C activity (BAT oxidative index) and BAT fractional (C) and net (D) glucose uptake.

Figure 3. Sympathetic nervous system-mediated WAT lipolysis and BAT and skeletal muscle metabolism

A–F, Spearman correlation between whole-body changes in R_a,NEFA (ΔR_a,NEFA) and BAT volume of activity (A), change in total BAT oxidative metabolism index (B), BAT total glucose uptake (C), shivering intensity (D), PET-determined shivering index (E) and skeletal muscle total glucose uptake (F). With the exclusion of one outlier in C, indicated by an open circle, r = 0.73, P = 0.02.

Figure 4. Bio-distribution of glucose and muscle shivering during cold exposure

A and D, glucose partitioning in BAT, subcutaneous WAT (scWAT) and skeletal muscles during cold exposure. B, shivering intensity of m. pectoralis major, m. trapezius, m. sternocleidomastoid (n = 9), m. rectus femoris, m. vastus lateralis (n = 9), m. rectus abdominis, m. vastus medialis (n = 9) and m. deltoideus (n = 9), determined by sEMG. C, Spearman correlation between shivering intensity determined by surface EMG and a shivering index calculated using the relative uptake of ¹⁸FDG in skeletal muscles. Values are presented as mean ± SEM (n = 12, unless otherwise indicated). Different from BAT at *P ≤ 0.05, ** P ≤ 0.001; different from m. pectoralis major at ^‡‡P ≤ 0.05, ^‡P ≤ 0.001. Significant difference, ^##P ≤ 0.001.

Figure 5. BAT and skeletal muscle glucose uptake

Total glucose uptake (A) and plasma glucose turnover (B) of skeletal muscle (red bar) and BAT (brown bar). Values presented as mean ± SEM (n = 12). Different from BAT at**P ≤ 0.001, ***P ≤ 0.0001.

Figure 6. BAT and skeletal muscle thermoregulatory interaction during cold exposure

A and B, Spearman correlation between cold-induced change in energy expenditure (Δ energy expenditure) and shivering intensity (A) and cold-induced BAT total oxidative index (Δ BAT total oxidative index, B). C and D, Spearman correlation between shivering intensity and BAT volume of activity (C) and cold-induced BAT total oxidative capacity (D).