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

Abstract

BACKGROUND. Mirabegron 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. METHODS. We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m 2) 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 [ 18 F]-2-fluoro-d-2-deoxy-d-glucose (18 F-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. RESULTS. Chronic 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. CONCLUSION. These 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 REGISTRATION. Clinicaltrials.gov NCT03049462.

Induction of Adipose Tissue Browning as a Strategy to Combat Obesity

“…CL-316243—a selective ADRB3 agonist was found to increase UCP1 mRNA synthesis in APCs and their differentiation towards brown adipocytes in vitro and induce WAT browning in rodents [ 19 , 122 ]. Recently another selective ADRB3 agonist—mirabegron, has been shown to increase BAT metabolic activity and energy expenditure in humans; however, the compound did not influence WAT browning [ 123 ]. In conclusion, despite promising preclinical data, selective ADRB3 agonists occurred to have limited efficacy in induction WAT browning in humans, probably due to the lower number of ADRB3 in human AT than in transfected cell-lines used for the in vitro experiments as well as different browning potential of WAT in rodents [ 124 ].…”

Inulin Supplementation Disturbs Hepatic Cholesterol and Bile Acid Metabolism Independent from Housing Temperature

“…In a process termed adaptive thermogenesis, uncoupling of the respiratory chain in BAT expends high amounts of energy and results in heat production. Of note, activation of BAT lowers plasma glucose and triglyceride levels and reduces insulin resistance [ 1 , 2 , 3 ]. Furthermore, activation of BAT by its natural stimulus cold, promotes cholesterol elimination via triggering hepatic remnant lipoprotein uptake and increasing hepatic bile acid synthesis, as well as fecal bile acid excretion.…”

Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

“…In humans, the activity of BAT has been repeatedly reported to be inversely associated with body mass index (Betz and Enerback, 2011;Tam et al, 2012). Chronic treatment with the β 3-adrenergic receptor agonist Mirabegron increases BAT activity and insulin sensitivity in young adults (O'Mara et al, 2020). Nonetheless, the factor that human BAT, including peri-scapular, peri-jugular and perirenal depots, undergoes age-related involution/atrophy raises doubts about the physiological significance of BAT, particularly in middle-aged humans.…”