PMID- 36150559 OWN - NLM STAT- MEDLINE DCOM- 20221018 LR - 20221026 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 192 DP - 2022 Nov 1 TI - FAM96A is essential for maintaining organismal energy balance and adipose tissue homeostasis in mice. PG - 115-129 LID - S0891-5849(22)00593-7 [pii] LID - 10.1016/j.freeradbiomed.2022.09.011 [doi] AB - The iron (Fe) metabolism plays important role in regulating systemic metabolism and obesity development. The Fe inside cells can form iron-sulfur (Fe-S) clusters, which are usually assembled into target proteins with the help of a conserved cluster assembly machinery. Family with sequence similarity 96A (FAM96A; also designated CIAO2A) is a cytosolic Fe-S assembly protein involved in the regulation of cellular Fe homeostasis. However, the biological function of FAM96A in vivo is still incompletely defined. Here, we tested the role of FAM96A in regulating organismal Fe metabolism, which is relevant to obesity and adipose tissue homeostasis. We found that in mice genetically lacking FAM96A globally, intracellular Fe homeostasis was interrupted in both white and brown adipocytes, but the systemic Fe level was normal. FAM96A deficiency led to adipocyte hypertrophy and organismal energy expenditure reduction even under nonobesogenic normal chow diet-fed conditions. Mechanistically, FAM96A deficiency promoted mechanistic target of rapamycin (mTOR) signaling in adipocytes, leading to an elevation of de novo lipogenesis and, therefore, fat mass accumulation. Furthermore, it also caused mitochondrial defects, including defects in mitochondrial number, ultrastructure, redox activity, and metabolic function in brown adipocytes, which are known to be critical for the control of energy balance. Moreover, adipocyte-selective FAM96A knockout partially phenocopied global FAM96A deficiency with adipocyte hypertrophy and organismal energy expenditure defects but the mice were resistant to high-fat diet-induced weight gain. Thus, FAM96A in adipocytes may autonomously act as a critical gatekeeper of organismal energy balance by coupling Fe metabolism to adipose tissue homeostasis. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Liu, Zhuanzhuan AU - Liu Z AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 109014180@qq.com. FAU - Xu, Shihong AU - Xu S AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 1158970638@qq.com. FAU - Zhang, Zhiwei AU - Zhang Z AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 1723477040@qq.com. FAU - Wang, Hanying AU - Wang H AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 1582717445@qq.com. FAU - Jing, Qiyue AU - Jing Q AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 544437964@qq.com. FAU - Zhang, Shenghan AU - Zhang S AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 846511041@qq.com. FAU - Liu, Mengnan AU - Liu M AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 2284173525@qq.com. FAU - Han, Jinzhi AU - Han J AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 709474304@qq.com. FAU - Kou, Yanbo AU - Kou Y AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 330624083@qq.com. FAU - Wei, Yanxia AU - Wei Y AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: 470368479@qq.com. FAU - Wang, Lu AU - Wang L AD - Peking University Center for Human Disease Genomics, Beijing, China; Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China. Electronic address: wanglu@bjmu.edu.cn. FAU - Wang, Yugang AU - Wang Y AD - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: wangyg@xzhmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220920 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Carrier Proteins) RN - 0 (Fam96a protein, mouse) RN - 70FD1KFU70 (Sulfur) RN - E1UOL152H7 (Iron) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - *Adipose Tissue/metabolism MH - Adipose Tissue, Brown MH - Animals MH - Carrier Proteins/metabolism MH - Diet, High-Fat/adverse effects MH - *Energy Metabolism MH - Homeostasis MH - Hypertrophy/metabolism MH - Iron/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Obesity/metabolism MH - Sirolimus/metabolism MH - Sulfur/metabolism MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - Adipose tissue OT - Energy expenditure OT - Iron metabolism OT - Iron-sulfur assembly protein OT - Mitochondria OT - brown adipocytes COIS- Declaration of competing interest 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- 2022/09/24 06:00 MHDA- 2022/10/19 06:00 CRDT- 2022/09/23 19:34 PHST- 2022/08/07 00:00 [received] PHST- 2022/09/13 00:00 [revised] PHST- 2022/09/14 00:00 [accepted] PHST- 2022/09/24 06:00 [pubmed] PHST- 2022/10/19 06:00 [medline] PHST- 2022/09/23 19:34 [entrez] AID - S0891-5849(22)00593-7 [pii] AID - 10.1016/j.freeradbiomed.2022.09.011 [doi] PST - ppublish SO - Free Radic Biol Med. 2022 Nov 1;192:115-129. doi: 10.1016/j.freeradbiomed.2022.09.011. Epub 2022 Sep 20.