Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androsta...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2016-05, Vol.30 (5), p.533-542
Main Authors: Mo, Li, Shen, Jing, Liu, Qinhui, Zhang, Yuwei, Kuang, Jiangying, Pu, Shiyun, Cheng, Shihai, Zou, Min, Jiang, Wei, Jiang, Changtao, Qu, Aijuan, He, Jinhan
Format: Article
Language:English
Subjects:
Adenosine Monophosphate - metabolism
Adipocytes - metabolism
AMP-Activated Protein Kinases - metabolism
Animals
Diet, High-Fat
Fibronectins - metabolism
Gluconeogenesis - physiology
Glucose - metabolism
Insulin Resistance - physiology
Lipid Metabolism - physiology
Lipogenesis - physiology
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Mice, Transgenic
Nuclear Reactors
Obesity - metabolism
Original Research
Receptors, Cytoplasmic and Nuclear - metabolism
RNA, Messenger - metabolism
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Summary:Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androstane receptor induced FNDC5 mRNA expression in the liver and increased the circulating level of irisin in mice. FNDC5/irisin is a direct transcriptional target of constitutive androstane receptor. Hepatic-released irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the Adenosine 5′-monophosphate (AMP)-activated protein kinase pathway. Adenovirus-overexpressed irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high-fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2015-1292