Mirabegron (Myrbetriq), an oral drug approved by the FDA in 2012 for treating incontinence, may offer a novel approach to weight management by enhancing the metabolic activity of brown fat, a specialized type of fat that promotes energy expenditure. This article delves into the potential role of mirabegron in weight loss, examining the existing research, mechanisms of action, and clinical implications.
Brown Fat and Energy Expenditure
Unlike the more prevalent white fat, brown fat possesses the unique ability to accelerate metabolism, especially when exposed to cold temperatures. While initially believed to be primarily present in babies and young children, scientists from Joslin Diabetes Center and other institutions discovered in 2009 that adults also have these cells. Animal studies have revealed that brown fat cells can be activated by various agents, including drugs that interact with a protein on the cell surface known as the Beta3-adrenergic receptor (β3-AR).
Activating Brown Fat with Mirabegron
Researchers at Joslin Diabetes Center 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), also known as brown fat, burns calories from fat and sugar to produce heat and is typically activated when a person is exposed to cold. The drug boosted energy consumption by more than 10% at peak effect, suggesting it might aid in weight loss.
This groundbreaking report demonstrated that human brown fat could be activated through targeted pharmacological intervention. Anti-obesity medications typically work by suppressing energy intake (EI), promoting energy expenditure (EE), or both. Metformin (Met) and mirabegron (Mir) induce weight loss by targeting EI and EE, respectively.
Combination Therapy: Metformin and Mirabegron
A study explored the anti-obesity effects, metabolic benefits, and underlying mechanisms of combining Metformin (Met) and Mirabegron (Mir) in both prevention and treatment models.
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Prevention Model
In a prevention model, Met/Mir caused a further 12% and 14% reduction in body weight 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. 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.
The Potential of Combination Therapy
Lifestyle modifications are essential to tackling obesity, but due to their difficulty and inherent limitations, they have achieved limited success in maintaining long‐term weight loss. Pharmacotherapy is therefore needed to improve the efficacy of lifestyle interventions for individuals with obesity. Combination therapy could be a promising option, suppressing food intake to induce weight loss. This is direct clinical evidence of the superiority of combination therapy in obesity treatment, necessitating further investigation into other possible drug combinations.
Brown adipose tissue (BAT) and beige white adipose tissue (WAT) have been increasingly recognized as critical regulators of whole‐body metabolism and EE and are considered promising targets for anti‐obesity therapeutics. BAT is enriched with mitochondria in which uncoupling protein 1 (UCP1) is highly expressed. Therefore, Mir is a promising candidate drug to promote weight loss by boosting EE.
The study used Met as an EI suppressant and Mir as an EE booster to investigate the combined effects of Met/Mir in preventing obesity development as well as in treating established DIO in mice. Several metabolic parameters were measured and investigated the underlying molecular mechanisms, with a special focus on pathways involved in thermogenesis. The safety of this combination treatment, especially on potential cardiovascular side effects was also evaluated. The results showed that Met/Mir produced additive effects on the prevention and treatment of obesity compared with monotherapy with either drug, with minimal side effects observed.
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Effects on Body Weight and Composition in Mice
Mice were fed a HFD and simultaneously received daily gavage with vehicle (Veh), Met, Mir, or Met/Mir for 12 weeks. The body weight (BW) of drug‐treated mice was significantly lower than that of Veh‐treated mice under HFD feeding. HFD‐fed mice treated with Met or Mir alone showed 24% (6.8 g) or 23% (6.3 g) less BW gain, respectively, when compared to the Veh‐treated mice. Importantly, Met/Mir‐treated mice displayed 37% less BW gain, which was a further 12% (3.2 g) and 14% (3.6 g) reduction in weight gain when compared to either Met or Mir alone.
Metformin (Met)/mirabegron (Mir) has an additive effect on preventing weight gain in the prevention model. No drug treatment altered lean mass, but Met and Mir mice had 49% (7.1 g) and 56% (8.0 g) less fat mass than Veh mice (14.4 g), respectively. Met/Mir treatment markedly reduced fat mass by 72% (10.4 g), although this reduction was not significant compared to Met and Mir mono‐treatment.
These results were further confirmed by the dissected weights of major white fat depots (subcutaneous, epidydimal, and retroperitoneal). In particular, Met, Mir, and Met/Mir treatments considerably decreased subcutaneous WAT (scWAT) by 0.89 g (-67%), 0.80 g (-60%), and 0.98 g (-73%), respectively. Despite a lack of statistical significance, Met/Mir treatment produced a greater reduction in fat mass than monotherapy. The Met, Mir, and Met/Mir treatments reduced the epidydimal WAT (eWAT) weight by 0.74 g (-42%), 0.98 g (-55%), and 1.32 g (74%), respectively, when compared to the Veh treatment. Similar results were observed in retroperitoneal WAT (rWAT), which was reduced by 0.27 g (-48%), 0.35 g (-62%), and 0.45 g (-80%) in Met, Mir, and Met/Mir mice, respectively, compared to Veh mice. Of note, there was a non‐significant decrease in BAT weight in Met, Mir, or Met/Mir mice compared to Veh mice. Taken together, Met/Mir prevents BW gain in an additive manner in HFD‐fed mice, which is mainly caused by a lower fat mass.
Impact on Energy Intake and Expenditure
Since obesity occurs under a long‐term energy imbalance, the effects of Met/Mir on EI and EE were evaluated. 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.
When compared to Veh, 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. 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.
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Met/Mir mice displayed a significant increase in food intake and EE when compared to their Met counterparts. To determine whether this elevated EE was caused by food-induced thermogenesis that was associated with increased food intake, a 2-week HFD pair-feeding experiment was performed in a separate cohort of wild-type mice where an equal amount of food was given to all the mice. Met caused no change in O2 consumption, CO2 release or EE, whereas Mir caused an elevation in O2 consumption, CO2 release, and EE. When compared to Veh or Met mice, both Mir and Met/Mir mice displayed a non-significant increase in O2 consumption, CO2 release, and EE within 6 h post-drug administration. Interestingly, only Met/Mir significantly decreased the RER suggesting a strong promotion of lipid oxidation. No difference in physical activity was observed among the groups. All findings clearly demonstrate that the enhanced EE in the Met/Mir treatment is independent of increased food intake.
Influence 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. Under pair-feeding, Met did not alter 6-h FBG levels, while Mir and Met/Mir significantly reduced them, but no further difference was observed under Met/Mir compared to either Met or Mir alone. 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. Additionally, after all treatments, hepatic glycogen content was not altered by Met, Mir, or Met/Mir. Collectively, these data confirm that the effect of Met/Mir on improved glycemic control is independent of food intake.
Thermogenesis, Lipolysis, and Fatty Acid Oxidation
To gain insight into how Met/Mir generates metabolic benefits under HFD feeding, the expression of key genes involved in thermogenesis, lipolysis, and fatty acid oxidation in BAT and WAT was assessed. 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, which was confirmed by UCP1 protein levels. 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.
Browning of WAT, especially subcutaneous fat depots, increases thermogenesis and EE and improves glucose tolerance. The expression of key beige fat markers in scWAT was evaluated. Compared to Veh, Met caused a non-significant decrease in Ucp1 mRNA and protein levels, 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. However, when compared to the Veh group, UCP1 protein levels in all three drug treatment groups were slightly increased, but there was no difference between drug treatment groups.
Mirabegron and Brown Fat Activation in Humans
Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. A study 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.
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.
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.
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, we were 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.
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.
Mirabegron and Beige Fat Formation
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. 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. 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.
When the researchers examined how mirabegron treatment affected certain molecular markers known to be present in beige fat, they saw an increase in several of these markers in white adipose tissue, indicating the formation of beige fat cells in response to the drug. These changes correlated with the improved glucose metabolism.
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.
This study demonstrated for the first time in people with overweight/obesity and insulin-resistance that mirabegron treatment improves multiple measures of glucose metabolism by inducing beige fat formation in white adipose tissue. In contrast to the increase in beige fat, an increase in brown fat was not observed in this study, but another recent study conducted by intramural NIDDK researchers demonstrated that brown fat is activated by mirabegron in a group of healthy women.
Cautions
While the early research on mirabegron and weight loss is promising, it's important to note several points:
- Limited Human Data: More extensive clinical trials are needed to confirm these findings and determine the long-term efficacy and safety of mirabegron for weight loss.
- Individual Variability: Responses to mirabegron may vary significantly between individuals.
- Approved Use: Mirabegron is currently approved for overactive bladder and not for weight loss. Using it for off-label purposes should only be done under the guidance of a healthcare professional.
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