Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue

Abstract

While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).

Keywords: brown fat; cardiometabolic diseases; energy expenditure; glucose metabolism; indirect calorimetry; lipoprotein metabolism; positron emission tomography; propranolol; responders.

Graphical abstract

Figure 1

Study design and timeline of study procedures (A) This study had a randomized, double-blinded, crossover design. (B) Both study visits started with the measurement of blood pressure and heart rate (indicated by the ECG icon). Thereafter, the first blood sample (indicated by blood drop icon) was drawn, followed by an indirect calorimetry measurement for 30 min. Then, participants received either placebo or propranolol (80 mg, in two capsules; per oral, PO), depending on the study visit. After 75 min, blood pressure and heart rate were measured again, and a single bolus of salbutamol (250 μg; intravenous, IV) was injected over a continuous time course of 5 min. 15 min after initiation of the injection, a low-dose computed tomography (CT) scan was performed, directly followed by injection of 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG; 185 MBq) and a dynamic positron emission tomography (PET) acquisition, during which heart rate was monitored. After termination of the scan, blood pressure and heart rate were measured, the final blood sample was drawn, and indirect calorimetry was performed for 30 min.

Figure 2

The effect of salbutamol vs. salbutamol with propranolol on heart rate, blood pressure, energy expenditure, and nutrient oxidation rates (A, C–G)The direct change in heart rate (n = 10) (A) and change over the study day of heart rate (n = 9) (C), systolic blood pressure (SBP) (n = 10) and diastolic blood pressure (DBP) (n = 9) (D), energy expenditure (EE) (n = 9) (E), fatty acid oxidation (FATox) (n = 9) (F), and carbohydrate oxidation (CHOox) (n = 9) (G) after salbutamol (red bars with circles) vs. salbutamol with propranolol (green bars with diamonds). For one participant, EE measurement failed due to technical issues. In one participant, a measurement of heart rate at the end of the study after salbutamol with propranolol is missing. General linear models with repeated measures and pairwise comparisons were used to test the effect of treatment and to compare the treatment regimens. Bars represent means, circles/diamonds represent individual values, and gray lines represent paired data. Before vs. after treatment: ^фp ≤ 0.05, ^ффp ≤ 0.01, ^фффp ≤ 0.001. Salbutamol vs. salbutamol with propranolol: ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001. (B) The effect of salbutamol (n = 10; red circles) vs. salbutamol with propranolol (n = 9; green diamonds) on heart rate over time. Vertical dashed line represents the moment of the administration of salbutamol. General linear model with repeated measures was used to test for an interaction between treatment regime and the effect of treatment over time. Bars represent means, and error bars represent SD.

Figure 3

The effect of salbutamol vs. salbutamol with propranolol on glucose uptake by brown adipose tissue, skeletal muscle, and subcutaneous white adipose tissue and the association with the change in energy expenditure (A) The glucose uptake by human brown adipose tissue (BAT), skeletal muscle (i.e., average of m. pectoralis, m. trapezius, m. deltoideus, and m. sternocleidomastoideus), and subcutaneous white adipose tissue (scWAT) after salbutamol (n = 10) vs. salbutamol with propranolol (n = 10). A paired Student’s t test, or nonparametric equivalent, was used to compare the two treatment regimes. Bars represent means, dots/diamonds represent individual values, and gray lines represent paired data. ∗p ≤ 0.05. (B) Positron emission tomography images of the supraclavicular area illustrating the [¹⁸F]fluorodeoxyglucose [¹⁸F]FDG uptake, expressed by body-weighted standardized uptake values (SUVs), in response to salbutamol (top) and salbutamol with propranolol (bottom). The same representative participant is presented for both images. White arrows show supraclavicular BAT depots. (C) Time-activity curve showing the concentration of [¹⁸F]FDG in BAT depots. Left and right, and all participants (n = 10) are averaged. Data represent mean with SEM. (D and E) Correlation plots between the change in energy expenditure (EE) (%) and the glucose uptake by human BAT after salbutamol (D) and skeletal muscle (SM) after salbutamol (E) (n = 9). For one participant, EE measurement failed due to technical issues. (F and G) Correlation plots between the change in EE and the glucose uptake by human BAT after salbutamol with propranolol (F) and SM after salbutamol with propranolol (G) (n = 9).

Figure 4

Differences in body composition and baseline serum lipid concentrations between non-responders and responders in terms of salbutamol-induced glucose uptake by brown adipose tissue (A) Waterfall plot showing the distribution in net glucose uptake by supraclavicular brown adipose tissue (BAT; left and right averaged). Each bar represents the individual value of a participant. (B–D) Differences in body fat mass percentage (B), waist-hip ratio (C), and baseline serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and free fatty acids (FFA) (D) between participants who showed a high salbutamol-induced net glucose uptake by brown adipose tissue (“responders,” blue bars with circles; n = 5) vs. participants who showed low salbutamol-induced net glucose uptake by brown adipose tissue (“non-responders,” white bars with triangles; n = 5). Values illustrated in the figures were measured at baseline during the placebo-visit. A paired Student’s t test, or nonparametric equivalent, was used to compare the two groups. Bars represent means, and error bars represent SD. ∗p ≤ 0.05, ∗∗p ≤ 0.01.

Figure 5

The effect of salbutamol vs. salbutamol with propranolol on serum concentrations of lipid and glucose metabolism The effect of salbutamol (red bars with circles; n = 10) vs. salbutamol with propranolol (green bars with diamonds; n = 10) on serum concentrations of triglycerides (TG; A), free fatty acids (FFA; B), total cholesterol (TC; C), high-density lipoprotein cholesterol (HDL-C; D), low-density lipoprotein cholesterol (LDL-C, E), glucose (F), insulin (G), and C-peptide (H). General linear models with repeated measures and pairwise comparisons were used to test the effect of treatment and to compare the treatment regimens. Bars represent means, dots/diamonds represent individual values, and gray lines represent the paired nature of the data. Start vs. end: ^ффp ≤ 0.01, ^фффp ≤ 0.001. Salbutamol vs. salbutamol with propranolol: ∗p ≤ 0.05, ∗∗p ≤ 0.01.