Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism

Yoon Keun Cho, Young Cheol Yoon, Hyeonyeong Im, Yeonho Son, Minsu Kim, Abhirup Saha, Cheoljun Choi, Jaewon Lee, Sumin Lee, Jae Hyun Kim, Yun Pyo Kang, Young-Suk Jung, Hong Koo Ha, Je Kyung Seong (), James G. Granneman (), Sung Won Kwon () and Yun-Hee Lee ()
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Yoon Keun Cho: Seoul National University
Young Cheol Yoon: Seoul National University
Hyeonyeong Im: Seoul National University
Yeonho Son: Seoul National University
Minsu Kim: Seoul National University
Abhirup Saha: Seoul National University
Cheoljun Choi: Seoul National University
Jaewon Lee: Seoul National University
Sumin Lee: Seoul National University
Jae Hyun Kim: Kangwon National University
Yun Pyo Kang: Seoul National University
Young-Suk Jung: Pusan National University
Hong Koo Ha: Pusan National University
Je Kyung Seong: Seoul National University
James G. Granneman: Wayne State University
Sung Won Kwon: Seoul National University
Yun-Hee Lee: Seoul National University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.

Date: 2022
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DOI: 10.1038/s41467-022-31805-3

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