The rising rates of obesity are a global health epidemic. In the US alone, by 2030 it is predicted that 86% of adults will be overweight or obese. Comorbidities include impaired glucose tolerance, dyslipidemia, hypertension, and a proinflammatory state. Addressing these problems with behavioral interventions alone has been largely unsuccessful, highlighting the need in many patients for adjunct therapy to maintain long-term improvements in obesity-related metabolic disease. One complementary approach has been pharmacological treatment to increase fatty acid and glucose oxidation. For several decades, an attractive target has been the β3-adrenergic receptor (β3-AR), whose activation in rodents leads to increased energy expenditure and improved glucose tolerance. Translation of the β3-AR rodent studies to humans has not been straightforward. Species differences in drug selectivity, oral bioavailability, and gene expression were limiting factors for achieving weight loss. Nevertheless, early-phase clinical trials showed improved glucose tolerance and increased fatty acid oxidation. Mirabegron, a β3-adrenergic receptor (β3-AR) agonist approved for the treatment of overactive bladder, has emerged as a potential therapeutic agent for weight loss and metabolic improvement. This article explores the effects of mirabegron on brown adipose tissue (BAT) activity, energy expenditure, glucose homeostasis, and overall weight management, drawing upon recent studies and findings.
Brown and Beige Adipose Tissue Activation
Brown and beige adipose tissues contain thermogenic fat cells that can be activated by β3-adrenergic receptor agonists. Researchers have shown that treatment with the drug mirabegron, which is approved to treat overactive bladder, stimulates the formation of beige fat tissue in people with insulin-resistance and overweight/obesity resulting in several metabolic health benefits, including improved blood glucose (sugar) metabolism. Among different types of fat tissue, brown fat is a form of fat that burns calories (energy) to generate heat unlike white fat, which is more abundant in the body and stores energy. Beige fat cells, which have similar energy-burning properties to brown fat, can be formed in white fat by cold exposure or through activation of the protein β (beta)3 adrenergic receptor (β3AR), which is present in fat cells and some bladder cells and can be stimulated by mirabegron.
Impact on BAT Metabolic Activity and Volume
Chronic mirabegron therapy has been shown to increase BAT metabolic activity. In a study involving healthy women, chronic mirabegron therapy increased BAT metabolic activity. The prespecified primary endpoint, the subjects’ detectable BAT metabolic activity as measured via [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT, significantly increased, with a median of 195 to 473 mL•g/mL (P = 0.039). Similar proportional increases in BAT volume were observed, with a median of 72 to 149 mL (P = 0.036), and maximum metabolic activity, with a median of 10 to 29 g/mL (P = 0.017). The extent of changes in BAT activity and volume were not the same across the group. The women who had less BAT on day 1 had larger increases than did those who started with more (R2 = 0.65 and 0.71, respectively, for activity and volume, both P < 0.001). These patterns suggest that chronic mirabegron treatment is particularly effective at increasing BAT activity in subjects who had little BAT before treatment, but there may also be an upper threshold in its efficacy.
Effects on Other Tissues
The PET/CT imaging also allowed us to measure metabolic activities of other tissues that can contribute to thermogenesis. In contrast to BAT, 18F-FDG uptake in erector spinae skeletal muscle was unchanged (-0.01 ± 0.05 g/mL, P = 0.77) and was lower in the dorsal-lumbar depot of subcutaneous WAT (scWAT) (-0.15 ± 0.04 g/mL, P = 0.006). The reason for the assessment of scWAT glucose uptake in particular was to determine whether there had been a detectable increase in thermogenic adipocytes in this very large depot. Human thermogenic adipocytes can originate from 2 distinct lineages: constitutive “brown” adipocytes in the cervical and supraclavicular regions and recruitable “beige/brite” adipocytes in the supraclavicular and abdominal depots as well as other, smaller sites (13-18). Without biopsies, it was unable to make a direct distinction between these 2 cell types or determine whether the increased metabolic activity was due to hypertrophy or hyperplasia. Given the wide distribution of activation, it is likely that both brown and beige/brite adipocytes contributed to the higher metabolic activity.
Impact on Energy Expenditure and Metabolism
Resting Energy Expenditure (REE) and Respiratory Quotient (RQ)
To evaluate how mirabegron affected whole-body metabolism, a repeated-measures ANOVA was used to determine the effects of the day of study, the time, and their interaction on resting energy expenditure (REE). A significant effect of both time of day (P < 0.001) and the interaction between the day of study and the time of day (P = 0.001) was observed: the initial dose of mirabegron on day 1 increased the REE by 10.7% (+6.4 ± 1.2 kcal/h, P < 0.001), yet the day-28 dose of mirabegron did not further increase the REE above the day-28 pre-dose baseline (0.8% = 0.5 ± 1.2 kcal/h, P = 0.70). The acute dose of mirabegron on both day 1 and day 28 lowered the RQ (-0.069 ± 0.007 and -0.051 ± 0.007, respectively; both P < 0.001), indicating a net increase in fat oxidation. In contrast to the results for REE, the baseline RQ on day 28 was not different from the RQ on day 1. Whole-body REE was higher, without changes in body weight or composition.
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Effects on Glucose Metabolism
Recent studies in mice have demonstrated that beige fat cells can improve glucose metabolism. Investigators recruited 13 women and men, who had overweight/obesity along with either prediabetes or metabolic syndrome, and treated them with mirabegron at the maximal dose approved (50 mg/day) for 12 weeks. Following mirabegron treatment, more than half of the participants who had prediabetes prior to treatment no longer met criteria for that condition. This finding was consistent with overall improvement of glucose tolerance, a marker of how well the body handles blood glucose. Researchers then further examined the participants to measure the function of β cells, which produce the insulin necessary for processing glucose, and how well other tissues respond to insulin (insulin sensitivity). The results indicated that an improvement in both measures led to the improved glucose tolerance. Mirabegron treatment improves multiple measures of glucose metabolism by inducing beige fat formation in white adipose tissue. Typically, improved glucose tolerance in people with prediabetes or type 2 diabetes is associated with weight loss. However, interestingly, the participants in this study did not experience weight loss. The combined metformin/mirabegron treatment not only prevents the development of diet‐induced obesity but also promotes weight loss in established diet‐induced obesity. Furthermore, metformin/mirabegron treatment induces a greater reduction in body weight than either treatment when used alone. 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.
Combination Therapy with Metformin
Combination therapy could be a promising option. Metformin (Met) and mirabegron (Mir) cause weight loss by targeting EI and EE, respectively. In this study, the anti‐obesity effects, metabolic benefits, and underlying mechanisms of Met/Mir combination therapy in two clinically relevant contexts: the prevention model and the treatment model were investigated. Metformin (Met)/mirabegron (Mir) has an additive effect on preventing weight gain in the prevention model.
Prevention Model
In the prevention model, Met/Mir caused further 12% and 14% reductions in body weight (BW) gain induced by a high‐fat diet compared to Met or Mir alone, respectively.
Treatment Model
In the treatment model, Met/Mir additively promoted 17% BW loss in diet‐induced obese mice, which was 13% and 6% greater than Met and Mir alone, respectively. Additionally, Met/Mir improved glucose tolerance and insulin sensitivity. These benefits of Met/Mir were associated with increased EE, activated brown adipose tissue thermogenesis, and white adipose tissue browning. Significantly, Met/Mir did not cause cardiovascular dysfunction in either model.
Effects on Energy Balance
Since obesity occurs under a long‐term energy imbalance, the effects of Met/Mir on EI and EE were evaluated next. Met decreased food intake, while Mir had no impact on food intake compared to Veh. Interestingly, Met's appetite‐suppressing effect was abolished when Met was combined with Mir. Notably, no difference in water consumption was observed across all groups (Figures S1). Mir, or Met/Mir caused significantly elevated O2 consumption, CO2 release, and EE when data were expressed as an hourly average and as a 12‐ or 24‐h average post‐drug administration when compared to Veh. Noticeably, Met/Mir mice had the highest O2 consumption, CO2 release, and EE among all groups. This suggests that Mir has a dominant effect on EE when used with Met. The respiratory exchange ratio (RER), an indicator of metabolic fuel preference, displayed no difference among all groups. Met/Mir mice displayed a significant increase in food intake and EE when compared to their Met counterparts. All findings clearly demonstrate that the enhanced EE in the Met/Mir treatment is independent of increased food intake.
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Effects on Glucose Metabolism in Combination
We therefore investigated whether Met/Mir has an additive effect on glucose metabolism. As expected, compared to Veh, Met, and Mir alone significantly decreased FBG; however, Met/Mir did not produce an additional effect on FBG. Met or Mir alone significantly improved glucose tolerance, as observed by lower blood glucose excursion and confirmed by the area under the curve (AUC), yet no further improvement was seen by Met/Mir treatment. Interestingly, while all drug‐treated mice displayed increased insulin responsiveness, Met/Mir mice had a further improvement when compared to monotherapy mice. Veh mice did not have HFD‐induced elevation in blood glucose due to limited HFD consumption. Met and Mir monotherapy reduced basal blood glucose on day 11, and a similar reduction was observed under Met/Mir treatment. When compared to Veh, Met slightly improved glucose tolerance, while Mir significantly enhanced glucose tolerance, and Met/Mir caused a strong trend toward an improvement in glucose tolerance (p = 0.0523). No effect on insulin responsiveness was observed among all groups. Collectively, these data confirm that the effect of Met/Mir on improved glycemic control is independent of food intake.
Effects on Gene Expression in Adipose Tissue
To gain insight into how Met/Mir generates metabolic benefits under HFD feeding, we assessed the expression of key genes involved in thermogenesis, lipolysis, and fatty acid oxidation in BAT and WAT. In BAT, both Met alone and Mir alone caused a non‐significant trend of increased Ucp1 mRNA expression, while Met/Mir significantly upregulated its expression. For other thermogenic markers, when compared to Veh, Met increased the mRNA expression of Cidea, and Mir increased that of Elovl3; Met/Mir significantly upregulated the mRNA levels of Prdm16, Dio2, Cidea, and Elovl3. Consistent with the observed enhancement of thermogenesis, Met/Mir significantly elevated the expression of Atgl and Hsl, two key regulators in lipolysis, and a panel of markers involved in mitochondrial fatty acid oxidation, including Acox1, Acsl1, Cpt1α, Cpt1β, and Cpt2. Compared to Veh, Met caused a non‐significant decrease in Ucp1 mRNA, whereas Mir significantly increased the mRNA levels of Ucp1, Prdm16, Dio2, and Cidea. The mRNA expression of these genes was comparable between Mir and Met/Mir. However, in contrast to mRNA levels, UCP1 protein levels were not significantly altered. Met decreased the mRNA expression of lipolytic genes in scWAT. was also downregulated while other fatty acid oxidation genes were unaffected. In eWAT, Mir alone and Met/Mir significantly boosted the mRNA levels of several markers involved in WAT browning, including Ucp1, Dio2, Cidea, Ppdm16, and Cox7a1.
Limitations and Considerations
It is important to note that while mirabegron shows promise in activating BAT and improving glucose metabolism, studies in humans have not consistently demonstrated significant weight loss. In this issue of the JCI, O’Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved β3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. A team of investigators led by Joslin Diabetes Center researchers and funded in part by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases successfully activated brown adipose tissue and increased energy expenditure in 12 lean adult men using mirabegron, a drug that stimulates β3-adrenergic receptors. Brown adipose tissue (BAT), often called brown fat, consumes calories from fat and sugar to generate heat and is normally activated when a person is exposed to cold. The scientists then examined effects on skeletal muscle, and they found that mirabegron treatment induced a beneficial switch in the type of muscle fibers in this tissue, which could account for improvements in insulin sensitivity in muscle. Remarkably, neither β cells nor skeletal muscle cells have the β3AR protein-and thus the beneficial effects of the drug must have been indirect, likely via mirabegron-induced changes in fat tissue.
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