Insulin-like growth factor-1 directly mediates expression of mitochondrial uncoupling protein 3 via forkhead box O4. (June 2019)

• Record Type: Journal Article
• Authors: Watamoto, Yukiko; Futawaka, Kumi; Hayashi, Misa; Matsushita, Midori; Mitsutani, Mana; Murakami, Kana; Song, Zilin; Koyama, Rie; Fukuda, Yuki; Nushida, Ayaka; Nezu, Syoko; Kuwahara, Akiko; Kataoka, Kazusaburo; Tagami, Tetsuya; Moriyama, Kenji
• Is Part Of: Growth hormone & IGF research. Volume 46/47(2019)
• Page Start: 24
• Page End: 35
• Publication Date: 2019-06
• Subjects: Energy metabolism -- Signal transduction -- Muscle specific gene; aFOXO4 constitutively active forkhead box O-4 -- Akt serine/threonine kinase Akt -- ANOVA analysis of variance -- BLAST Basic Local Alignment Search Tool -- DMEM Dulbecco's Modified Eagle's Medium -- FOXO4 Forkhead box O-4 -- GH growth hormone -- IGF-1 insulin-like growth factor-1 -- IRS insulin reactive substances -- IGF-1R insulin/insulin-like growth factor-1 receptor -- PI3K phosphatidylinositol 3 kinase -- qRT-PCR quantitative reverse-transcription polymerase chain reaction -- SD standard deviation -- UCP mitochondria uncoupled protein; Growth regulators -- Periodicals; Growth -- Regulation -- Periodicals; Somatomedin -- Periodicals; Somatomedins -- Periodicals; Growth Hormone -- Periodicals; Growth Substances -- Periodicals; Croissance -- Régulation -- Périodiques; Croissance -- Régulateurs -- Périodiques; Somatotrophine -- Périodiques; Somatomédine -- Périodiques; Growth -- Regulation; Growth regulators; Electronic journals; Periodicals; Electronic journals; 612.4
• DOI: 10.1016/j.ghir.2019.05.003
• Languages: English
• ISSNs: 1096-6374

Abstract

Abstract: Objective: The objective of our study was to examine the direct action of insulin-like growth factor-1(IGF-1) signaling on energy homeostasis in myocytes. Design: We studied the IGF-1 stimulation of mitochondrial uncoupling protein 3 (UCP3) expression in the HEK 293 derived cell line TSA201, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal myoblasts. We also investigated the direct effect of IGF-1 on the Insulin/IGF-1 receptor (IGF-1R)/phosphatidylinositol 3 (PI3)-Akt/forkhead box O4 (FOXO4) pathway using a combination of a reporter assay, semi-quantitative polymerase chain reaction, western blotting, and animal experiments. Results: We demonstrated that IGF-1 regulates UCP3 expression via phosphorylation of FOXO4, which is a downstream signal transducer of IGF-1. UCP3 expression increased with activated FOXO4 in a dose-dependent manner. We also examined the functional FOXO4 binding site consensus sequences and identified it as the −1922 bp site in the UCP3 promoter region. UCP3 was also found to be concomitantly expressed with IGF-1 during differentiation of C2C12 myoblasts. Our animal experiments showed that high fat diet induced IGF-1 levels which likely influenced UCP3 expression in the skeletal muscle. Conclusion: Our findings demonstrate that that IGF-1 directly stimulates UCP3 expression via the IGF-1/IGF-1R/PI3-Akt/FOXO4 pathway. Highlights: FOXO4 acts downstream of PI3K-Akt and is involved in IGF-1-mediated energy metabolism. IGF-1 regulates the expression of UCP3 and its impact was greater than that of GH. IGF-1 may play some kind of roles locally in myoblasts differentiation in association with UCP3.