Abstract
Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders. These people store fat in subcutaneous adipose tissue (SAT) rather than in visceral adipose tissue (VAT). However, the molecules participating in this specific scenario remain elusive. Rab18, a lipid droplet (LD)-associated protein, mediates the contact between the endoplasmic reticulum (ER) and LDs to facilitate LD growth and maturation. In the present study, we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice. Rab18 adipocyte-specific knockout (Rab18 AKO) mice had a decreased volume ratio of SAT to VAT compared with wildtype mice. When subjected to high-fat diet (HFD), Rab18 AKO mice had increased ER stress and inflammation, reduced adiponectin, and decreased triacylglycerol (TAG) accumulation in SAT. In contrast, TAG accumulation in VAT, brown adipose tissue (BAT) or liver of Rab18 AKO mice had a moderate increase without ER stress stimulation. Rab18 AKO mice developed insulin resistance and systematic inflammation. Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT, similar to the counterpart mice. Furthermore, Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress, indicating the involvement of Rab18 in alleviating lipid toxicity. Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT. In conclusion, our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.
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Acknowledgement
This work was supported by the National Key Research and Development Program of China (2018YFA0506901, 2019YFA0801701, 2022YFA0806502), the National Natural Science Foundation of China (92254308, 92157107), and the Lingang Laboratory (LG-QS-202204-06). We would like to thank the members of the P.L. laboratory at Tsinghua University for productive discussion; Dr. Yuangang Zhu at Peking University for guiding EM analysis and Dr. Tongjin Zhao for manuscript editing.
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The authors declare no conflict of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All applicable institutional and/or national guidelines for the care and use of animals were followed.
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Liu, J., Li, L., Xu, D. et al. Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2367-9
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DOI: https://doi.org/10.1007/s11427-023-2367-9