title: Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis.
abstract: Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.
authors: Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore.
authors: J
authors: J
authors: Huo
authors: Institute of Biomedicine, Ji Nan University, 601 HUANG PO DA DAO XI, Guang Zhou 510632, P.R. China.
authors: Y
authors: Y
authors: Ma
authors: Clinical Research Unit, Khoo Teck Puat Hospital, ALEXANDRA HEALTH PTE LTD, 90 Yishun Central, Singapore 768828, Singapore.
authors: J-J
authors: JJ
authors: Liu
authors: Metabolomics Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #02-01 Centros, Singapore 138668, Singapore.
authors: Y S
authors: YS
authors: Ho
authors: Clinical Research Unit, Khoo Teck Puat Hospital, ALEXANDRA HEALTH PTE LTD, 90 Yishun Central, Singapore 768828, Singapore.
authors: S
authors: S
authors: Liu
authors: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 11 Biopolis Way, Helios, Singapore 138667, Singapore.
authors: L Y
authors: LY
authors: Soh
authors: Metabolomics Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #02-01 Centros, Singapore 138668, Singapore.
authors: S
authors: S
authors: Chen
authors: Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore.
authors: S
authors: S
authors: Xu
authors: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 11 Biopolis Way, Helios, Singapore 138667, Singapore.
authors: W
authors: http://orcid.org/0000-0002-5023-2104
authors: W
authors: Han
authors: Institute of Biomedicine, Ji Nan University, 601 HUANG PO DA DAO XI, Guang Zhou 510632, P.R. China.
authors: A
authors: A
authors: Hong
authors: Diabetes Center, Khoo Teck Puat Hospital, ALEXANDRA HEALTH PTE LTD, 90 Yishun Central, Singapore 768828, Singapore.
authors: S C
authors: SC
authors: Lim
authors: Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore.|Department of Physiology, National University of Singapore, NUS Yong Loo Lin School of Medicine, Block MD9, 2 Medical Drive #04-01, Singapore 117597, Singapore.|Department of Microbiology, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 3, Singapore 117545, Singapore.|School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors: K-P
authors: KP
authors: Lam
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050155:Lipogenesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; C498892:Faim protein, mouse; D007328:Insulin