황성순 (Salk Institute for Biological Studies)

한빛사논문

조회4,193

Salk Institute for Biological Studies

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Nat. Med., Published online 05 January 2015, | doi:10.1038/nm.3760 Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

Abstract

Sungsoon Fang¹, Jae Myoung Suh¹, Shannon M Reilly², Elizabeth Yu¹, Olivia Osborn³, Denise Lackey³, Eiji Yoshihara¹, Alessia Perino⁴, Sandra Jacinto¹, Yelizaveta Lukasheva¹, Annette R Atkins¹, Alexander Khvat⁵, Bernd Schnabl³, Ruth T Yu¹, David A Brenner³, Sally Coulter⁶, Christopher Liddle⁶, Kristina Schoonjans⁴, Jerrold M Olefsky³, Alan R Saltiel², Michael Downes¹ & Ronald M Evans^1,7

¹Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. ²Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA. ³Department of Medicine, University of California San Diego, San Diego, California, USA. ⁴Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Switzerland. ⁵ChemDiv, Inc., San Diego, California, USA.⁶Storr Liver Unit, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Australia. ⁷Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.

Correspondence to : Michael Downes or Ronald M Evans

Abstract
The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

논문정보

형식Research article
게재일2015년 01월 (BRIC 등록일 2015-01-08)
연구진국외 연구진
분야 생명과학 > 세포생물학

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