Tip60-mediated Rheb acetylation links palmitic acid with mTORC1 activation and insulin resistance
Excess dietary intake of saturated fatty acids (SFAs) induces glucose intolerance and metabolic disorders. In contrast, unsaturated fatty acids (UFAs) elicit beneficial effects on insulin sensitivity. However, it remains elusive how SFAs and UFAs signal differentially toward insulin signaling to influence glucose homeostasis. Here, using a croaker model, we report that dietary palmitic acid (PA), but not oleic acid or linoleic acid, leads to dysregulation of mTORC1, which provokes systemic insulin resistance. Mechanistically, we show that PA profoundly elevates acetyl-CoA derived from mitochondrial fatty acid β oxidation to intensify Tip60-mediated Rheb acetylation, which triggers mTORC1 activation by promoting the interaction between Rheb and FKBPs. Subsequently, hyperactivation of mTORC1 enhances IRS1 serine phosphorylation and inhibits TFEB-mediated IRS1 transcription, inducing impairment of insulin signaling. Collectively, our results reveal a conserved molecular insight into the mechanism by which Tip60-mediated Rheb acetylation induces mTORC1 activation and insulin resistance under the PA condition, which may provide therapeutic avenues to intervene in the development of T2D.
Authors
- Yongtao Liu
- Qiangde Liu
- Ya-nan Shen
- Zengqi Zhao (ORCID: https://orcid.org/0000-0003-3497-7496)
- Qinghui Ai (ORCID: https://orcid.org/0000-0002-3958-474X)
- Kangsen Mai (ORCID: https://orcid.org/0000-0002-4597-543X)
- Wei Fang (ORCID: https://orcid.org/0009-0000-4139-0699)
- Qiang Chen (ORCID: https://orcid.org/0009-0000-7791-8598)
- Xiaojun Xiang (ORCID: https://orcid.org/0000-0002-8544-6401)
- Kun Cui
- Baolin Li (ORCID: https://orcid.org/0000-0001-7735-6716)
- Yueru Li (ORCID: https://orcid.org/0000-0002-1535-6099)
- Weiwei Dai
- Wei Xu (ORCID: https://orcid.org/0000-0002-2864-6247)
Institutions
- Harvard University (US)
- Ministry of Agriculture and Rural Affairs (CN)
- Ocean University of China (CN)
- Xi’an Jiaotong-Liverpool University (CN)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2024-08-31
- DOI
- https://doi.org/10.1083/jcb.202309090
- Citations
- 14
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 4.13
Funders
- Purdue University
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Fudan University
- Tsinghua University
- Ocean University of China
- Peking University
- Agriculture Research System of China
- Recruitment Program of Global Experts
- Institute of Zoology, Chinese Academy of Sciences
- Kunming Institute of Zoology, Chinese Academy of Sciences
- National Science Fund for Distinguished Young Scholars
- National Ten Thousand Talent Program