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ABSTRACT
Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.
Abbreviations
| BECN1 | = | beclin 1, autophagy related |
| CMA | = | chaperone-mediated autophagy |
| EE | = | energy expenditure |
| eWAT | = | epididymal WAT |
| FFAs | = | free fatty acids |
| HFD | = | high-fat diet |
| iWAT | = | inguinal WAT |
| LAMP2A | = | lysosomal-associated membrane protein 2A |
| LDs | = | lipid droplets |
| LRRK2 | = | leucine-rich repeat kinase 2 |
| MAP1LC3/LC3 | = | microtubule-associated protein 1 light chain 3 |
| RILP | = | Rab interacting lysosomal protein |
| SQSTM1/p62 | = | sequestosome 1 |
| T-CHO | = | total cholesterol |
| TG | = | triglycerides |
| TIGAR | = | Trp53 induced glycolysis regulatory phosphatase |
| WAT | = | white adipose tissue. |
Acknowledgements
We thank Dr. Yu-E Wang for her technical guidance on the preparation of the nano-emulsion. We also would like to thank the support from the National Natural Science Foundation of China, Excellent Young Talents Plan of Guizhou Medical University, China Postdoctoral Science Foundation, Guizhou Provincial Innovation and Entrepreneurship Projects for Overseas Talents, Guizhou Provincial Science and Technology Projects, Guizhou Provincial Health Commission Science and Technology Foundation and Guizhou Provincial Natural Science Foundation.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Supplementary Material:
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2338576