puc-header

Human BAT Thermogenesis is Stimulated by the β 2-Adrenergic Receptor

43 Pages Posted: 23 Aug 2019 Sneak Peek Status: Review Complete

See all articles by Denis P. Blondin

Denis P. Blondin

Université de Sherbrooke - Centre de recherche

Mai C. Severinsen

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Eline N. Kuipers

Leiden University - Division of Endocrinology

Verena H. Jensen

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Stéphanie Miard

Université Laval - Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec

Naja Z. Jespersen

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Sander Kooijman

Leiden University - Division of Endocrinology

Mariette R. Boon

Leiden University - Division of Endocrinology

Mélanie Fortin

Université de Sherbrooke - Centre de recherche

Serge Phoenix

Université de Sherbrooke - Centre de recherche

Frédérique Frisch

Université de Sherbrooke - Centre de recherche

Brigitte Guérin

Université de Sherbrooke - Department of Nuclear Medicine and Radiobiology

Éric E. Turcotte

Université de Sherbrooke - Department of Nuclear Medicine and Radiobiology

François Haman

University of Ottawa - Faculty of Health Sciences

Denis Richard

Université Laval - Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec

Frédéric Picard

Université Laval - Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec

Patrick C.N. Rensen

Leiden University - Division of Endocrinology

Camilla Scheele

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

André C. Carpentier

Université de Sherbrooke; Université de Sherbrooke - Faculty of Medicine and Health Sciences

More...

Abstract

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergic receptor (β3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of the β3-AR but rather driven primarily through the β2-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. Such a dose led to off-target binding to the β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. In vitro pharmacological stimulation as well as pharmacological and genetic inhibition of the β2-AR in human primary brown adipocytes all confirmed that this β-AR subtype is essential to simulate BAT lipolysis and thermogenesis in humans (ClinicalTrials.gov NCT02811289).

Keywords: brown adipose tissue, β2-adrenergic receptor, energy metabolism, positron emission tomography

Suggested Citation

Blondin, Denis P. and Severinsen, Mai C. and Kuipers, Eline N. and Jensen, Verena H. and Miard, Stéphanie and Jespersen, Naja Z. and Kooijman, Sander and Boon, Mariette R. and Fortin, Mélanie and Phoenix, Serge and Frisch, Frédérique and Guérin, Brigitte and Turcotte, Éric E. and Haman, François and Richard, Denis and Picard, Frédéric and Rensen, Patrick C.N. and Scheele, Camilla and Carpentier, André C., Human BAT Thermogenesis is Stimulated by the β 2-Adrenergic Receptor (August 21, 2019). CELL-METABOLISM-D-19-00916. Available at SSRN: https://ssrn.com/abstract=3440265 or http://dx.doi.org/10.2139/ssrn.3440265
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Denis P. Blondin

Université de Sherbrooke - Centre de recherche

Sherbrooke
Canada

Mai C. Severinsen

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Blegdamsvej 3B
Copenhagen, DK-2200
Denmark

Eline N. Kuipers

Leiden University - Division of Endocrinology

Leiden
Netherlands

Verena H. Jensen

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Blegdamsvej 3B
Copenhagen, DK-2200
Denmark

Stéphanie Miard

Université Laval - Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec

Québec
Canada

Naja Z. Jespersen

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Blegdamsvej 3B
Copenhagen, DK-2200
Denmark

Sander Kooijman

Leiden University - Division of Endocrinology

Leiden
Netherlands

Mariette R. Boon

Leiden University - Division of Endocrinology

Leiden
Netherlands

Mélanie Fortin

Université de Sherbrooke - Centre de recherche

Sherbrooke
Canada

Serge Phoenix

Université de Sherbrooke - Centre de recherche

Sherbrooke
Canada

Frédérique Frisch

Université de Sherbrooke - Centre de recherche

Sherbrooke
Canada

Brigitte Guérin

Université de Sherbrooke - Department of Nuclear Medicine and Radiobiology

Sherbrooke
Canada

Éric E. Turcotte

Université de Sherbrooke - Department of Nuclear Medicine and Radiobiology

Sherbrooke
Canada

François Haman

University of Ottawa - Faculty of Health Sciences

Ottawa, Ontario
Canada

Denis Richard

Université Laval - Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec

Québec
Canada

Frédéric Picard

Université Laval - Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec

Québec
Canada

Patrick C.N. Rensen

Leiden University - Division of Endocrinology

Leiden
Netherlands

Camilla Scheele

University of Copenhagen - The Novo Nordisk Foundation Center for Basic Metabolic Research

Blegdamsvej 3B
Copenhagen, DK-2200
Denmark

André C. Carpentier (Contact Author)

Université de Sherbrooke

2500 bd de l'Universite
Sherbrooke, J1K 2R1
Canada

Université de Sherbrooke - Faculty of Medicine and Health Sciences ( email )

Canada

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
190
Downloads
15