Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity

Abstract

BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Keywords: Adipose tissue; Cholesterol; Endocrinology; Glucose metabolism; Metabolism.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Flow diagram and study design.

(A) Flow diagram describing the numbers and disposition of the study subjects. (B) On day 0 and day 27, the subjects underwent metabolic testing consisting of a FSIGT test, a liver scan, an exercise tolerance test (VO2max), and DXA. The subjects then entered the metabolic chamber at 1800 hours and remained overnight and through 1400 hours on day 1 and day 28, after which they were transported to the PET/CT suite. Blood was drawn to measure metabolites before treatment on day 1 and day 28 at 0800 hours and then just prior to 18F-FDG administration in the chamber at 1300 hours. Mirabegron was administered at 0900 hours. The black bars above the diagrams refer to the 30-minute still periods during which the REE was measured. The black arrows indicate the time points at which blood was drawn for pharmacokinetic measurements.

Figure 2. Mirabegron pharmacokinetics.

Plasma concentration of mirabegron during day 1 (black circles, dashed black line), on interim visit day 14 (blue triangle), and during day 28 (green squares, green line). The Ki of mirabegron is 55 nM. Values represent the mean ± SEM. n = 12. * P < 0.05, ** P < 0.01, and *** P < 0.001, by paired Student’s t test.

Figure 3. Effects of chronic mirabegron treatment on BAT, skeletal muscle, and scWAT.

(A) PET images on day 1 and day 28 for 2 representative subjects; magenta arrowheads point to the supraclavicular BAT depot with low (top) and high (bottom) initial BAT 18F-FDG uptake after an acute dose of mirabegron. Detectable BAT (B) metabolic activity and (C) volume in subjects on day 1 (black circles) and day 28 (black squares). Both y axes are shown using a log10 scale. P values correspond to the paired Student’s t test on the log10-transformed data, which was the prespecified analysis. SUVmax in (D) BAT, (E) erector spinae skeletal muscle, and (F) dorsolumbar scWAT from PET/CT scans of subjects performed on day 1 and day 28. Individual volume was measured on day 1 (black circles) and day 28 (black squares); red bars represent group medians for BAT and means for skeletal muscle and WAT. P values were determined using a paired Student’s t test. n = 14.

Figure 4. Effects of chronic mirabegron treatment on REE and RQ.

Changes in (A) REE and (B) RQ in response to 100 mg oral mirabegron on day 1 (circles) and day 28 (squares) as measured in a metabolic chamber during 20-minute still periods at 0800 hours (white circles and squares) and 1300 hours (black circles and squares). Red bars represent group means. A repeated-measures ANOVA was used to determine the effects of the day of study, the time, and their interaction. n = 14.

Figure 5. FSIGT outcomes.

Plasma (A) glucose and (B) insulin responses during a FSIGT test on day 0 (circles, black line) and day 27 (squares, green line). Error bars indicate the SEM. The inset in A shows the levels from 0 to 10 minutes after injection of glucose. Individual changes in (C) SG, (D) whole-body SI, (E) AIRG, and (F) the DI. Red bars represent group means. Comparisons for each time point in A and B (* P < 0.05) and between day 0 (white circles) and day 27 (white squares) in C–F were made using a paired Student’s t test. n = 12.