Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adi-pocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling–mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in perox-isome proliferator–activated receptor a signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.
|Number of pages||14|
|Publication status||Published - 2021 Sept|
Bibliographical noteFunding Information:
Funding. This research was supported by National Research Foundation of Korea grants (NRF-2019R1C1C1002014, NRF-2018R1A5A2024425, NRF-2013M3A9D5072550) funded by the Korean government (Ministry of Science and ICT). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Y.-H.L. conceived and designed the study. C.C., Y.S., J.K., Y.K.C., A.S., M.K., H.I., K.K., J.H., J.W.L., and J.K.S. conducted the animal experiments. C.C. and Y.S. performed in vitro experiments. J.W.L. supplied the TSAHC reagent. C.C. and Y.-H.L. wrote the manuscript. All authors reviewed the manuscript. Y.-H.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
© 2021 by the American Diabetes Association.
All Science Journal Classification (ASJC) codes
- Internal Medicine
- Endocrinology, Diabetes and Metabolism