PMID- 38496880 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240319 IS - 2405-8440 (Print) IS - 2405-8440 (Electronic) IS - 2405-8440 (Linking) VI - 10 IP - 6 DP - 2024 Mar 30 TI - Untargeted metabolomics uncovers metabolic dysregulation and tissue sensitivity in ACE2 knockout mice. PG - e27472 LID - 10.1016/j.heliyon.2024.e27472 [doi] LID - e27472 AB - Angiotensin-converting enzyme 2 (ACE2) polymorphisms are associated with increased risk of type 2 diabetes mellitus (T2DM), obesity and dyslipidemia, which have been determined in various populations. Consistently, ACE2 knockout (ACE2 KO) mice display damaged energy metabolism in multiple tissues, especially the key metabolic tissues such as liver, skeletal muscle and epididymal white adipose tissue (eWAT) and show even more severe phenotype under high-fat diet (HFD) induced metabolic stress. However, the effects of ACE2 on global metabolomics profiling and the tissue sensitivity remain unclear. To understand how tissues independently and collectively respond to ACE2, we performed untargeted metabolomics in serum in ACE2 KO and control wild type (WT) mice both on normal diet (ND) and HFD, and in three key metabolic tissues (liver, skeletal muscle and eWAT) after HFD treatment. The results showed significant alterations in metabolic profiling in ACE2 KO mice. We identified 275 and 168 serum metabolites differing significantly between WT and ACE2 KO mice fed on ND and HFD, respectively. And the altered metabolites in the ACE2 KO group varied from 90 to 196 in liver, muscle and eWAT. The alterations in ND and HFD serum were most similar. Compared with WT mice, ACE2 KO mice showed an increase in N-phenylacetylglutamine (PAGln), methyl indole-3-acetate, 5-hydroxytryptophol, cholic acid, deoxycholic acid and 12(S)-HETE, while LPC (19:0) and LPE (16:1) decreased. Moreover, LPC (20:0), LPC (20:1) and PC (14:0e/6:0) were reduced in both ND and HFD serum, paralleling the decreases identified in HFD skeletal muscle. Interestingly, DL-tryptophan, indole and Gly-Phe decreased in both ND and HFD serum but were elevated in HFD liver of ACE2 KO mice. A low level of l-ergothioneine was observed among liver, muscle, and epididymal fat tissue of ACE2 KO mice. Pathway analysis demonstrated that different tissues exhibited different dysregulated metabolic pathways. In conclusion, these results revealed that ACE2 deficiency leads to an overall state of metabolic distress, which may provide a new insight into the underlying pathogenesis in metabolic disorders in both ACE2 KO mice and in patients with certain genetic variant of ACE2 gene. CI - (c) 2024 The Authors. FAU - Zhao, Lili AU - Zhao L AD - Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. FAU - Yang, Weili AU - Yang W AD - Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. FAU - Ji, Wenyi AU - Ji W AD - Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. FAU - Pan, Qiuyue AU - Pan Q AD - Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. FAU - Yang, Jinkui AU - Yang J AD - Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. FAU - Cao, Xi AU - Cao X AD - Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. LA - eng PT - Journal Article DEP - 20240308 PL - England TA - Heliyon JT - Heliyon JID - 101672560 PMC - PMC10944221 OTO - NOTNLM OT - ACE2 OT - Gene knockout OT - Glucolipid metabolism OT - Metabolomics OT - T2DM COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/03/18 06:44 MHDA- 2024/03/18 06:45 PMCR- 2024/03/08 CRDT- 2024/03/18 04:44 PHST- 2023/12/04 00:00 [received] PHST- 2024/02/20 00:00 [revised] PHST- 2024/02/29 00:00 [accepted] PHST- 2024/03/18 06:45 [medline] PHST- 2024/03/18 06:44 [pubmed] PHST- 2024/03/18 04:44 [entrez] PHST- 2024/03/08 00:00 [pmc-release] AID - S2405-8440(24)03503-5 [pii] AID - e27472 [pii] AID - 10.1016/j.heliyon.2024.e27472 [doi] PST - epublish SO - Heliyon. 2024 Mar 8;10(6):e27472. doi: 10.1016/j.heliyon.2024.e27472. eCollection 2024 Mar 30.