PMID- 36375515 OWN - NLM STAT- MEDLINE DCOM- 20221223 LR - 20221223 IS - 1872-7786 (Electronic) IS - 0009-2797 (Linking) VI - 369 DP - 2023 Jan 5 TI - High-fat diet and palmitate inhibits FNDC5 expression via AMPK-Zfp57 pathway in mouse muscle cells. PG - 110265 LID - S0009-2797(22)00470-7 [pii] LID - 10.1016/j.cbi.2022.110265 [doi] AB - Irisin, a muscle-secreted cytokine involved in maintaining glucose homeostasis and improving insulin resistance, is generated from the precursor fibronectin type Ⅲ domain-containing protein 5 (FNDC5) by specific proteases. Zinc-finger protein Zfp57, a transcription factor that maintains the methylation during early embryonic development, is also reported to be associated with diabetes mellitus. However, the association between Zfp57 and FNDC5 is still unclear. In our study, we explored the detailed regulatory effect of Zfp57 on FNDC5 expression. In this study, we found that high-fat diet or saturated fatty acid palmitate increased the Zfp57 expression and decreased FNDC5 expression in muscle tissue or C2C12 myotubes. RNA sequencing analysis disclosed effects of the high-fat diet on genes associated with insulin resistance and the AMP-activated protein kinase (AMPK) signaling pathway in muscle tissue of mice. Chromatin immunoprecipitation experiments revealed that Zfp57 binds the FNDC5 gene promoter at positions -308 to -188. Moreover, Zfp57 overexpression inhibited FNDC5 expression, and Zfp57 knockdown alleviated the inhibitory effect of palmitate on FNDC5 expression in C2C12 myotubes. In addition, in vivo and in vitro studies demonstrated that activation of the AMPK pathway by 5-Aminoimidazole-4-carboxamide riboside (AICAR) or metformin mitigated the inhibitory effect of Zfp57 on FNDC5 expression and improved insulin resistance. These findings collectively suggest that high-fat diet and palmitate inhibit the AMPK pathway to increase Zfp57 expression, which in turn induces FNDC5 inhibition, to further aggravate insulin resistance. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Guo, Qian AU - Guo Q AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China; Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, USA. FAU - Zhang, Boya AU - Zhang B AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Du, Haining AU - Du H AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Zhu, Ruijiao AU - Zhu R AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Sun, Xiaotong AU - Sun X AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Fan, Xingpei AU - Fan X AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Wei, Xiangjuan AU - Wei X AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Yang, DaQian AU - Yang D AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. FAU - Oh, Yuri AU - Oh Y AD - Faculty of Education, Wakayama University, Wakayama, Japan. FAU - Fan, Lei AU - Fan L AD - Department of Endocrinology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China. FAU - Wang, Changlin AU - Wang C AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. Electronic address: wangcl@hit.edu.cn. FAU - Gu, Ning AU - Gu N AD - School of Life Science and Technology, Harbin Institute of Technology, Harbin, China; State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China. Electronic address: guning@hit.edu.cn. LA - eng PT - Journal Article DEP - 20221112 PL - Ireland TA - Chem Biol Interact JT - Chemico-biological interactions JID - 0227276 RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - 0 (Palmitates) RN - 0 (Fibronectins) RN - 0 (Transcription Factors) RN - 0 (FNDC5 protein, mouse) SB - IM MH - Mice MH - Animals MH - *AMP-Activated Protein Kinases/metabolism MH - Palmitates/pharmacology MH - *Insulin Resistance MH - Fibronectins/metabolism MH - Diet, High-Fat/adverse effects MH - Muscle Fibers, Skeletal MH - Transcription Factors/metabolism MH - Muscle, Skeletal/metabolism OTO - NOTNLM OT - AMPK OT - FNDC5 OT - High-fat diet OT - Palmitate OT - Zfp57 COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/11/15 06:00 MHDA- 2022/12/24 06:00 CRDT- 2022/11/14 19:23 PHST- 2022/07/24 00:00 [received] PHST- 2022/11/03 00:00 [revised] PHST- 2022/11/11 00:00 [accepted] PHST- 2022/11/15 06:00 [pubmed] PHST- 2022/12/24 06:00 [medline] PHST- 2022/11/14 19:23 [entrez] AID - S0009-2797(22)00470-7 [pii] AID - 10.1016/j.cbi.2022.110265 [doi] PST - ppublish SO - Chem Biol Interact. 2023 Jan 5;369:110265. doi: 10.1016/j.cbi.2022.110265. Epub 2022 Nov 12.