Journal ArticleDOI
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
Mitsuhiro Watanabe,Sander M. Houten,Chikage Mataki,Marcelo A. Christoffolete,Brian W. Kim,Hiroyuki Sato,Nadia Messaddeq,John W. Harney,Osamu Ezaki,Tatsuhiko Kodama,Kristina Schoonjans,Antonio C. Bianco,Johan Auwerx +12 more
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TLDR
It is shown that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin, and indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators.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, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-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 1c. 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-alpha, 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.read more
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Functional interactions between the gut microbiota and host metabolism
TL;DR: Through increased knowledge of the mechanisms involved in the interactions between the microbiota and its host, the world will be in a better position to develop treatments for metabolic disease.
Journal ArticleDOI
AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity
Carles Cantó,Zachary Gerhart-Hines,Jerome N. Feige,Marie Lagouge,Liliana Noriega,Liliana Noriega,Jill C. Milne,Peter J. Elliott,Pere Puigserver,Johan Auwerx,Johan Auwerx +10 more
TL;DR: It is demonstrated that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1.
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Endocrine Regulation of Energy Metabolism by the Skeleton
Na Kyung Lee,Hideaki Sowa,Eiichi Hinoi,Mathieu Ferron,Jong Deok Ahn,Cyrille Confavreux,Romain Dacquin,Patrick J. Mee,Marc D. McKee,Dae Young Jung,Zhiyou Zhang,Jason K. Kim,Franck Mauvais-Jarvis,Patricia Ducy,Gerard Karsenty +14 more
TL;DR: It is shown that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity, and in vivo osteocalcin can improve glucose tolerance.
Journal ArticleDOI
What We Talk About When We Talk About Fat
TL;DR: New perspective is gained on the roles played by adipocyte in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues and how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.
Journal ArticleDOI
Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice
Zhanguo Gao,Jun Yin,Jin Jin Zhang,Robert Ward,Roy J. Martin,Michael Lefevre,William T. Cefalu,Jianping Ye +7 more
TL;DR: Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse and the mechanism ofbutyrate action is related to promotion of energy expenditure and induction of mitochondria function.
References
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Journal ArticleDOI
Identification of a Nuclear Receptor for Bile Acids
Makoto Makishima,Arthur Y. Okamoto,Joyce J. Repa,Hua Tu,R. Marc Learned,Alvin Luk,Mitchell V. Hull,Kevin D. Lustig,David J. Mangelsdorf,Bei Shan +9 more
TL;DR: Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor, which demonstrates a mechanism by which bile acid transcriptionally regulate their biosynthesis and enterohepatic transport.
Journal ArticleDOI
Bile Acids: Natural Ligands for an Orphan Nuclear Receptor
Derek J. Parks,Steven G. Blanchard,Randy K. Bledsoe,Gyan Chandra,Thomas G. Consler,Steven A. Kliewer,Julie B. Stimmel,Timothy M. Willson,Ann Marie Zavacki,David D. Moore,Jürgen M. Lehmann +10 more
TL;DR: Results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis and modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1.
Journal ArticleDOI
A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis
Bryan Goodwin,Stacey A. Jones,Roger R. Price,Michael A. Watson,D.D. McKee,Linda B. Moore,Cristin M. Galardi,Joan G. Wilson,Michael C. Lewis,Matthew E. Roth,Patrick R. Maloney,Timothy M. Willson,Steven A. Kliewer +12 more
TL;DR: A potent, nonsteroidal FXR ligand is used to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain that provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
Journal ArticleDOI
Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.
TL;DR: The goal of this review is to place the exciting advances that have occurred in understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context.
Journal ArticleDOI
Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.
TL;DR: It is suggested that FXR (BAR) is the endogenous biliary component that selectively activates the orphan nuclear receptor, FXR, and thus an important regulator of cholesterol homeostasis.
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