Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.
Sungsoon FangJae Myoung SuhShannon M ReillyElizabeth YuOlivia OsbornDenise LackeyEiji YoshiharaAlessia PerinoSandra JacintoYelizaveta LukashevaAnnette R AtkinsAlexander KhvatBernd SchnablRuth T YuDavid A BrennerSally CoulterChristopher LiddleKristina SchoonjansJerrold M OlefskyAlan R SaltielMichael DownesRonald M EvansPublished in: Nature medicine (2015)
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.
Keyphrases
- insulin resistance
- adipose tissue
- metabolic syndrome
- weight gain
- high fat diet induced
- high fat diet
- polycystic ovary syndrome
- type diabetes
- body mass index
- skeletal muscle
- weight loss
- birth weight
- oxidative stress
- magnetic resonance
- poor prognosis
- drug induced
- glycemic control
- genome wide
- computed tomography
- drug delivery
- cardiovascular disease
- magnetic resonance imaging
- preterm birth
- transcription factor
- cell therapy
- combination therapy
- low density lipoprotein
- replacement therapy
- mesenchymal stem cells