Estrogen-Related Receptors Mediate the Adaptive Response of Brown Adipose Tissue to Adrenergic Stimulation
Erin L. Brown,
Bethany C. Hazen,
Elodie Eury,
Jean-Sébastien Wattez,
Marin L. Gantner,
Verena Albert,
Sarah Chau,
Manuel Sanchez-Alavez,
Bruno Conti,
Anastasia Kralli
Affiliations
Erin L. Brown
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Bethany C. Hazen
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Elodie Eury
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Jean-Sébastien Wattez
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Marin L. Gantner
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Verena Albert
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Sarah Chau
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Manuel Sanchez-Alavez
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Bruno Conti
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Anastasia Kralli
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: Adrenergic stimulation of brown adipose tissue (BAT) induces acute and long-term responses. The acute adrenergic response activates thermogenesis by uncoupling oxidative phosphorylation and enabling increased substrate oxidation. Long-term, adrenergic signaling remodels BAT, inducing adaptive transcriptional changes that expand thermogenic capacity. Here, we show that the estrogen-related receptors alpha and gamma (ERRα, ERRγ) are collectively critical effectors of adrenergically stimulated transcriptional reprogramming of BAT. Mice lacking adipose ERRs (ERRαγAd−/−) have reduced oxidative and thermogenic capacity and rapidly become hypothermic when exposed to cold. ERRαγAd−/− mice treated long term with a β3-adrenergic agonist fail to expand oxidative or thermogenic capacity and do not increase energy expenditure in response to norepinephrine (NE). Furthermore, ERRαγAd−/− mice fed a high-fat diet do not lose weight or show improved glucose tolerance when dosed with β3-adrenergic agonists. The molecular basis of these defects is the finding that ERRs mediate the bulk of the transcriptional response to adrenergic stimulation. : Adrenergic Receptor Function; Biochemical Mechanism; Molecular Biology Subject Areas: Adrenergic Receptor Function, Biochemical Mechanism, Molecular Biology
