1. Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch, France
2. Department of Medicine, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
3. Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan
4. Laboratory for Systems Biology and Medicine, RCAST, University of Tokyo, Tokyo 153-8904, Japan
5. Institut Clinique de la Souris, 67404 Illkirch, France
6. *These authors contributed equally to this work

Correspondence to: Johan Auwerx^1,5 Correspondence and requests for materials should be addressed to J.A. (Email: auwerx@igbmc.u-strasbg.fr).

Abstract

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways^{1, 2}, are ligands for the G-protein-coupled receptor (GPCR) TGR5^{3, 4} and activate nuclear hormone receptors such as farnesoid X receptor (FXR-; NR1H4)^{5, 6, 7}. FXR- regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2)^{8, 9} that inhibits the activity of other nuclear receptors. The FXR--mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c¹⁰. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2^-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA–TGR5–cAMP–D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

1. Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch, France
2. Department of Medicine, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
3. Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan
4. Laboratory for Systems Biology and Medicine, RCAST, University of Tokyo, Tokyo 153-8904, Japan
5. Institut Clinique de la Souris, 67404 Illkirch, France
6. *These authors contributed equally to this work

Correspondence to: Johan Auwerx^1,5 Correspondence and requests for materials should be addressed to J.A. (Email: auwerx@igbmc.u-strasbg.fr).

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