The bone anabolic effects of irisin are through preferential stimulation of aerobic glycolysis

• Published in: Bone (New York, N.Y.) N.Y.), 2018-09, Vol.114, p.150-160
• Main Authors: Zhang, Dongdong, Bae, ChuHyun, Lee, Junghak, Lee, Jiho, Jin, Zeyu, Kang, Myeongmo, Cho, Young Suk, Kim, Jeong-Han, Lee, Weontae, Lim, Sung-Kil
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Aerobic glycolysis; Anabolic Agents - metabolism; Anabolic Agents - pharmacology; Anabolism; Animals; Cell Differentiation - drug effects; Cell Differentiation - physiology; Fibronectins - biosynthesis; Fibronectins - pharmacology; Glycolysis - drug effects; Glycolysis - physiology; Humans; Irisin; Mice; Osteoblast; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteogenesis - drug effects; Osteogenesis - physiology; TCA cycle
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2018.05.013

Irisin, a recently identified hormone secreted by skeletal muscle in response to exercise, exhibits anabolic effects on the skeleton primarily through the stimulation of bone formation. However, the mechanism underlying the irisin-stimulated anabolic response remains largely unknown. To uncover the underlying mechanism, we biosynthesized recombinant irisin (r-irisin) using an Escherichia coli expression system and used it to treat several osteoblast cell types. Our synthesized r-irisin could promote proliferation and differentiation of osteoblasts as evidenced by enhanced expression of osteoblast-specific transcriptional factors, including Runt-related transcription factor-2 (Runx2), Oster (Osx), as well as early osteoblastic differentiation markers such as alkaline phosphatase (Alp) and collagen type I alpha 1 (Col1a1). Furthermore, we showed that the promotion of r-irisin on the proliferation and differentiation of osteoblast lineage cells are preferentially through aerobic glycolysis, as indicated by the enhanced abundance of representative enzymes such as lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1), together with increased lactate levels. Suppression of r-irisin-mediated aerobic glycolysis with Dichloroacetate blunted its anabolic effects. The favorite of the aerobic glycolysis after r-irisin treatment was then confirmed in primary calvarial cells by metabolic analysis using gas chromatography–mass spectrometry. Thus, our results suggest that the anabolic actions of r-irisin on the regulation of osteoblast lineage cells are preferentially through aerobic glycolysis, which may help to develop new irisin-based bone anabolic agents. •Our produced r-irisin promoted proliferation and early differentiation of osteoblasts.•The r-irisin preferentially stimulated aerobic glycolysis.•Activation of aerobic glycolysis may be a common feature of bone anabolism.