Yoon Keun Cho1,7, Young Cheol Yoon1,7, Hyeonyeong Im1,7, Yeonho Son1, Minsu Kim1, Abhirup Saha1, Cheoljun Choi1, Jaewon Lee1, Sumin Lee1, Jae Hyun Kim2, Yun Pyo Kang1, Young-Suk Jung3, Hong Koo Ha4, Je Kyung Seong5,8,*, James G. Granneman6,8,*, Sung Won Kwon1,8,* & Yun-Hee Lee1,8,*
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. 2College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea. 3Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea. 4Department of Urology, Pusan National University Hospital, College of Medicine, Pusan National University, Busan, Republic of Korea. 5Korea Mouse Phenotyping Center (KMPC), and Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea. 6Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA. 7These authors contributed equally: Yoon Keun Cho, Young Cheol Yoon, Hyeonyeong Im. 8These authors jointly supervised this work: Je Kyung Seong, James G. Granneman, Sung Won Kwon, and Yun-Hee Lee.
*Corresponding author.
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.