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

Alana E. O'Mara; James W. Johnson; Joyce D. Linderman; Robert J. Brychta; Suzanne McGehee; Laura A. Fletcher; Yael A. Fink; Devika Kapuria; Thomas M. Cassimatis; Nathan Kelsey; Cheryl Cero; Zahraa Abdul Sater; Francesca Piccinini; Alison S. Baskin; Brooks P. Leitner; Hongyi Cai; Corina M. Millo; William Dieckmann; Mary Walter; Norman B. Javitt; Yaron Rotman; Peter J. Walter; Marilyn Ader; Richard N. Bergman; Peter Herscovitch; Kong Y. Chen; Aaron M. Cypess

doi:10.1172/JCI131126

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

Alana E. O'Mara, James W. Johnson, Joyce D. Linderman, Robert J. Brychta, Suzanne McGehee, Laura A. Fletcher, Yael A. Fink, Devika Kapuria, Thomas M. Cassimatis, Nathan Kelsey, Cheryl Cero, Zahraa Abdul Sater, Francesca Piccinini, Alison S. Baskin, Brooks P. Leitner, Hongyi Cai, Corina M. Millo, William Dieckmann, Mary Walter, Norman B. JavittYaron Rotman, Peter J. Walter, Marilyn Ader, Richard N. Bergman, Peter Herscovitch, Kong Y. Chen, Aaron M. Cypess

Division of Gastroenterology

Research output: Contribution to journal › Article › peer-review

267 Scopus citations

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/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. 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.

Original language	English
Pages (from-to)	2209-2219
Number of pages	11
Journal	Journal of Clinical Investigation
Volume	130
Issue number	5
DOIs	https://doi.org/10.1172/JCI131126
State	Published - May 1 2020

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O'Mara, A. E., Johnson, J. W., Linderman, J. D., Brychta, R. J., McGehee, S., Fletcher, L. A., Fink, Y. A., Kapuria, D., Cassimatis, T. M., Kelsey, N., Cero, C., Sater, Z. A., Piccinini, F., Baskin, A. S., Leitner, B. P., Cai, H., Millo, C. M., Dieckmann, W., Walter, M., ... Cypess, A. M. (2020). Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. Journal of Clinical Investigation, 130(5), 2209-2219. https://doi.org/10.1172/JCI131126

@article{429f502751ca47c285e19cee8b1684eb,

title = "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/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. 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.",

author = "O'Mara, {Alana E.} and Johnson, {James W.} and Linderman, {Joyce D.} and Brychta, {Robert J.} and Suzanne McGehee and Fletcher, {Laura A.} and Fink, {Yael A.} and Devika Kapuria and Cassimatis, {Thomas M.} and Nathan Kelsey and Cheryl Cero and Sater, {Zahraa Abdul} and Francesca Piccinini and Baskin, {Alison S.} and Leitner, {Brooks P.} and Hongyi Cai and Millo, {Corina M.} and William Dieckmann and Mary Walter and Javitt, {Norman B.} and Yaron Rotman and Walter, {Peter J.} and Marilyn Ader and Bergman, {Richard N.} and Peter Herscovitch and Chen, {Kong Y.} and Cypess, {Aaron M.}",

note = "Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = may,

day = "1",

doi = "10.1172/JCI131126",

language = "English",

volume = "130",

pages = "2209--2219",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

number = "5",

}

O'Mara, AE, Johnson, JW, Linderman, JD, Brychta, RJ, McGehee, S, Fletcher, LA, Fink, YA, Kapuria, D, Cassimatis, TM, Kelsey, N, Cero, C, Sater, ZA, Piccinini, F, Baskin, AS, Leitner, BP, Cai, H, Millo, CM, Dieckmann, W, Walter, M, Javitt, NB, Rotman, Y, Walter, PJ, Ader, M, Bergman, RN, Herscovitch, P, Chen, KY & Cypess, AM 2020, 'Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity', Journal of Clinical Investigation, vol. 130, no. 5, pp. 2209-2219. https://doi.org/10.1172/JCI131126

TY - JOUR

T1 - Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity

AU - O'Mara, Alana E.

AU - Johnson, James W.

AU - Linderman, Joyce D.

AU - Brychta, Robert J.

AU - McGehee, Suzanne

AU - Fletcher, Laura A.

AU - Fink, Yael A.

AU - Kapuria, Devika

AU - Cassimatis, Thomas M.

AU - Kelsey, Nathan

AU - Cero, Cheryl

AU - Sater, Zahraa Abdul

AU - Piccinini, Francesca

AU - Baskin, Alison S.

AU - Leitner, Brooks P.

AU - Cai, Hongyi

AU - Millo, Corina M.

AU - Dieckmann, William

AU - Walter, Mary

AU - Javitt, Norman B.

AU - Rotman, Yaron

AU - Walter, Peter J.

AU - Ader, Marilyn

AU - Bergman, Richard N.

AU - Herscovitch, Peter

AU - Chen, Kong Y.

AU - Cypess, Aaron M.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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/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. 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.

AB - 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/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. 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.

UR - http://www.scopus.com/inward/record.url?scp=85083360316&partnerID=8YFLogxK

U2 - 10.1172/JCI131126

DO - 10.1172/JCI131126

M3 - Article

C2 - 31961826

AN - SCOPUS:85083360316

SN - 0021-9738

VL - 130

SP - 2209

EP - 2219

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 5

ER -

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

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