Human adipose beiging in response to cold and mirabegron

Finlin, Brian S.; Memetimin, Hasiyet; Confides, Amy L.; Kasza, Ildikó; Zhu, Beibei; Vekaria, Hemendra J.; Harfmann, Brianna D.; Jones, Kelly A.; Johnson, Zachary R.; Westgate, Philip M.; Alexander, Caroline M.; Sullivan, Patrick G.; Dupont‐Versteegden, Esther E.; Kern, Philip A.

doi:10.1172/jci.insight.121510

Cited by 160 publications

(196 citation statements)

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“…Lipolysis is often triggered by fasting, exercise, and cold exposure, which mobilize the stored excessive energy for coping with increased metabolic rates. As a β3adrenoreceptor agonist, mirabegron has been shown in humans to be able to activate BAT and thermogenesis (31,32). In this work, we show that a clinical relevant dose of mirabegron can activate BAT and induce a browning phenotype in subWAT and visWAT in mice.…”

Section: Discussionmentioning

confidence: 51%

“…More recently, a causal link between anticholinergic burden and the development of dementia has been established (28)(29)(30), raising further concerns about the safety issue in human patients. Activation of the β3-adrenergic receptor also induces BAT activation and browning of WAT (31,32). In a recent pilot human study, it has been shown that a clinical dose of mirabegron can activate BAT and browning WAT in human subjects (32).…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

Sui

Yang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Mirabegron (Myrbetriq) is a β3-adrenoreceptor agonist approved for treating overactive bladder syndrome in human patients. This drug can activate brown adipose tissue (BAT) in adult humans and rodents through the β3-adrenoreceptor-mediated sympathetic activation. However, the effect of the mirabegron, approved by the US Food and Drug Administration, on atherosclerosis-related cardiovascular disease is unknown. Here, we show that the clinical dose of mirabegron-induced BAT activation and browning of white adipose tissue (WAT) exacerbate atherosclerotic plaque development. In apolipoprotein E −/− (ApoE −/− ) and low-density lipoprotein (LDL) receptor −/− (Ldlr −/− ) mice, oral administration of clinically relevant doses of mirabegron markedly accelerates atherosclerotic plaque growth and instability by a mechanism of increasing plasma levels of both LDL-cholesterol and very LDL-cholesterol remnants. Stimulation of atherosclerotic plaque development by mirabegron is dependent on thermogenesis-triggered lipolysis. Genetic deletion of the critical thermogenesis-dependent protein, uncoupling protein 1, completely abrogates the mirabegron-induced atherosclerosis. Together, our findings suggest that mirabegron may trigger cardiovascular and cerebrovascular diseases in patients who suffer from atherosclerosis. mirabegron | atherosclerosis | plaque instability | lipolysis | adipose tissue A therosclerosis, the thickening, hardening, and loss of elasticity of the arterial vessel wall, is the major cause of morbidity and mortality worldwide (1-4). Atherosclerotic lesions containing fatty plaques, cholesterol, and inflammatory cells are the primary causes of cardiovascular disease and stroke (5, 6). Atherosclerosis as a chronic and progressive disease usually starts with damage of the endothelial layer of an artery. Hypertension, hyperglycemia, hyperlipidemia especially hypercholesterolemia, smoking, obesity and diabetes, certain inflammatory disorders such as arthritis, infections, and drugs are the common risk factors of atherosclerotic plaque formation (7,8). Of interest, high incidences of myocardial infarction and stroke have been associated with colder ambient temperature and cold seasons (9, 10). Although the exact mechanism underlying low ambient temperature has not been elucidated, our recent findings show that cold-induced lipolysis in brown adipose tissue (BAT) and browning of white adipose tissue (WAT) may partly explain the high incidences of cardiovascular disease and stroke (11).The balance between energy deposition and dissipation is regulated by multiple factors, including the central nervous system, the endocrine system, food intake, physical exercise, pathological disease, and medications (12,13). Although WAT stores excessive energy in its lipid form, activated BAT specializes energy consumption by producing heat (14,15). Under certain conditions such as cold exposure, WAT, especially that located in the s.c. region, undergoes the brown-like transition, a process named browning WAT (16,17). Instead of stor...

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Section: Discussionmentioning

confidence: 51%

Section: Significancementioning

confidence: 99%

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

Sui

Yang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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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“…In a separate study, mitochondria from human abdominal subcutaneous WAT following cold exposure showed increased uncoupled and maximal respiration (Kern et al, ). There also appears to be a seasonal variation in UCP1 content in human subcutaneous WAT (Finlin et al, ; Kern et al, ), which also occurs in human adult BAT. Hence, there is some evidence of β‐adrenoceptor function in human brite adipocytes, but more research is warranted.…”

Section: Adrenoceptors In Human Adipose Tissuementioning

confidence: 99%

Adrenoceptors in white, brown, and brite adipocytes

Evans

Merlin

Bengtsson

et al. 2019

British J Pharmacology

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Adrenoceptors play an important role in adipose tissue biology and physiology that includes regulating the synthesis and storage of triglycerides (lipogenesis), the breakdown of stored triglycerides (lipolysis), thermogenesis (heat production), glucose metabolism, and the secretion of adipocyte‐derived hormones that can control whole‐body energy homeostasis. These processes are regulated by the sympathetic nervous system through actions at different adrenoceptor subtypes expressed in adipose tissue depots. In this review, we have highlighted the role of adrenoceptor subtypes in white, brown, and brite adipocytes in both rodents and humans and have included detailed analysis of adrenoceptor expression in human adipose tissue and clonally derived adipocytes. We discuss important considerations when investigating adrenoceptor function in adipose tissue or adipocytes. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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Human adipose beiging in response to cold and mirabegron

Abstract: NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).

Cited by 160 publications

References 61 publications

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis

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

Adrenoceptors in white, brown, and brite adipocytes

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