Acute metabolic and cardiovascular effects of mirabegron in healthy individuals

Loh, Rebecca; Formosa, Melissa F.; Gerche, André La; Reutens, Anne T.; Kingwell, Bronwyn A.; Carey, Andrew L.

doi:10.1111/dom.13516

Cited by 55 publications

(60 citation statements)

References 43 publications

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“…Higher levels of UCP1 and Complex I in the BAT detected here indicate a sustained effect of CL-316,243 on BAT thermogenesis after a onemonth chronic treatment in old mice. This is consistent with strong previous evidence that β3AR stimulation leads to increased thermogenic activity of BAT in young mice (Labbé et al, 2016;Poher et al, 2015;Xiao et al, 2015) and humans as well (Cypess et al, 2015;Loh et al, 2018). It also shows that chronic β3AR administration does not induce significant receptor desensitization, despite decreased levels of BAT β3AR following treatment, in agreement with previous works (Nedergaard and Cannon, 2013).…”

Section: β3ar Agonist: a Two In One Strategy To Target Both Metabolicsupporting

confidence: 93%

“…The most well-known characteristic of CL-316,243 is to improve metabolic disorders through enhanced BAT activity (Burkey et al, 2000;de Souza et al, 1997;Kim et al, 2006;Kumar et al, 2015;Labbé et al, 2016) (Cypess et al, 2015;Loh et al, 2018). Whether this effect is maintained with age remains unknown.…”

Section: β3ar Agonist: a Two In One Strategy To Target Both Metabolicmentioning

confidence: 99%

“…Indeed, one administration of mirabegron at a dose of 200 mg (fourth times the clinical dose) enhances BAT activity in adults, but also induced cardiac arrhythmia in a few cases (Cypess et al, 2015). While the clinical dose of 50 mg does not seem to be efficient to acutely stimulate BAT (Baskin et al, 2018), a recent study showed that 100 mg of mirabegron enhances thermogenesis without any cardiovascular side effects in adults (Loh et al, 2018). Yet, longterm studies investigating chronic effect of β3AR agonists in BAT thermogenesis in old volunteers are needed.…”

Section: Conclusion: Potential Translation To Clinicmentioning

confidence: 99%

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Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

Tournissac

Vrabic

et al. 2020

Preprint

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Old age, the most important risk factor for Alzheimer's disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through β3-adrenergic receptor (β3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a β3AR agonist could exert benefits in AD as well.Here, we show that β3AR agonist administration (CL-316,243, 1 mg/kg/day i.p., from 15 to 16 months of age) decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a β3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old).Locomotion, anxiety and tau pathology were not modified. Finally, insoluble Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice.Overall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.

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Section: β3ar Agonist: a Two In One Strategy To Target Both Metabolicsupporting

confidence: 93%

Section: β3ar Agonist: a Two In One Strategy To Target Both Metabolicmentioning

confidence: 99%

Section: Conclusion: Potential Translation To Clinicmentioning

confidence: 99%

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Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

Tournissac

Vrabic

et al. 2020

Preprint

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“…We were also able to elucidate the impact of sympathetic activation in the absence of any change in housing temperature by administering YM-178. This highly selective β3-agonist increases BAT activity, whole body EE and induces ‘browning’ in humans [28-31]. Administration of YM-178 to mice for 4-6 weeks at similar dosage to this study (i.e.…”

Section: Discussionmentioning

confidence: 99%

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

Aldiss

Lewis

Lupini

et al. 2019

Preprint

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Background and aim:Rodents are commonly housed below thermoneutrality and this exposure to 'cold' (i.e. 20°C) activates thermogenic brown (BAT) and beiging of white adipose tissue. Here, we examined whether a standard housing temperature (i.e. 20°C, a reduction in temperature of ~8°C) or YM-178, a highly-selective β 3-adrenoreceptor agonist, in obese animals raised at thermoneutrality, would impact differently on classical BAT or subcutaneous inguinal (IWAT) beige depots. Methods: Eighteen weanling Sprague-Dawley rats were housed at thermoneutrality (28°C) and fed a high-fat diet. At 12 weeks, 6 animals were randomised to either standard housing temperature (20°C, n=6) or to β 3-AR agonist administration (28°C+β3, 0.75mg/kg/d, n=6) for 4 weeks. Metabolic assessment was undertaken during the final 48h, followed by interscapular, perivascular BAT and IWAT sampling for the analysis of thermogenic genes and the proteome. Results: Exposure to 20°C increased weight gain, BAT and IWAT mass. Proteomic analysis of BAT revealed novel pathways associated with cold-induced weight gain (i.e. histone deacetylation, glycosaminoglycan degradation and glycosphingolipid biosynthesis) whilst β 3adrenoreceptor agonism impacted on proteins involved in skeletal muscle contraction and cell differentiation. IWAT of cold-exposed animals exhibited an enrichment of proteins involved NAD+ binding, plus retinol and tyrosine metabolic pathways whilst β 3-AR agonism downregulated ribosomal and upregulated acute phase response proteins. Conclusion: Following diet-induced obesity at thermoneutrality, exposure to 20°C promotes subcutaneous fat deposition in order to reduce heat loss and defend body temperature. In contrast, chronic administration of β 3-AR agonist has minimal metabolic-related effects on adipose tissue.

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“…While encouraging, there was an increase in heart rate and blood pressure that were not seen at the maximum approved dosage of 50 mg daily, which itself did not affect EE (154). It remains to be determined whether other doses of mirabegron will be clinically effective and safe, both acutely (155) and after chronic treatment (156).…”

Section: Sympathomimeticsmentioning

confidence: 96%

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity

Chen

Brychta

Sater

et al. 2020

Journal of Biological Chemistry

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The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

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Acute metabolic and cardiovascular effects of mirabegron in healthy individuals

Abstract: A 100-mg dose of mirabegron increases energy expenditure and supraclavicular skin temperature in a β3-adrenoceptor-specific manner, without the off-target elevations in blood pressure or heart rate observed at higher doses.

Cited by 55 publications

References 43 publications

Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity

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