Abstract

Irisin is a polypeptide hormone derived from the proteolytic cleavage of fibronectin-type III domain-containing 5 (FNDC5) protein. Once released to circulation upon exercise or cold exposure, irisin stimulates browning of white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression, leading to an increase in total body energy expenditure by augmented UCP1-mediated thermogenesis. It is currently unknown whether irisin is secreted by bone upon exercise or whether it regulates bone metabolism in vivo. In this study, we found that 2 weeks of voluntary wheel-running exercise induced high levels of FNDC5 messenger RNA as well as FNDC5/irisin protein expression in murine bone tissues. Increased immunoreactivity due to exercise-induced FNDC5/irisin expression was detected in different regions of exercised femoral bones, including growth plate, trabecular bone, cortical bone, articular cartilage, and bone–tendon interface. Exercise also increased expression of osteogenic markers in bone and that of UCP1 in WAT, and led to bodyweight loss. Irisin intraperitoneal (IP) administration resulted in increased trabecular and cortical bone thickness and osteoblasts numbers, and concurrently induced UCP1 expression in subcutaneous WAT. Lentiviral FNDC5 IP administration increased cortical bone thickness. In vitro studies in bone cells revealed irisin increases osteoblastogenesis and mineralization, and inhibits receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis. Taken together, our findings show that voluntary exercise increases irisin production in bone, and that an increase in circulating irisin levels enhances osteogenesis in mice.

Highlights

  • Adipose tissue is a major endocrine organ that regulates energy balance and energy homeostasis.[1]

  • A group of 5-week-old mice was subjected to 2 weeks of voluntary wheel running and compared with a control group under routine cage activity. quantitative real-time PCR (qRT-PCR) analyses revealed that fibronectin-type III domaincontaining 5 (FNDC5) and PGC1α messenger RNA (mRNA) levels were increased in bone tissue from the exercise group (Figure 1a)

  • The exercise protocol used in our study induced PGC1α/FNDC5/irisin signaling and expression of osteogenic markers in bone, and concurrently increased uncoupling protein 1 (UCP1) mRNA expression in subcutaneous white adipose tissue (WAT) and decreased average body weight

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Summary

Introduction

Adipose tissue is a major endocrine organ that regulates energy balance and energy homeostasis.[1]. WAT from certain depots contain “brite” adipocytes that upon stimulation can undergo a process referred to as “browning” where they take on characteristics of BAT, including the induction of UCP1 and the ability to dissipate energy through a thermogenic response.

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