ANGPTL6 expression is coupled with mitochondrial OXPHOS function to regulate adipose FGF21.
Recent studies revealed that the inhibition of mitochondrial oxidative phosphorylation (OXPHOS) is coupled with the mitochondrial unfolded protein response, thereby stimulating the secretion of non-cell autonomous factors, which may control systemic energy metabolism and longevity. However, the nature and roles of non-cell autonomous factors induced in adipose tissue in response to reduced OXPHOS function remain to be clarified in mammals. CR6-interacting factor 1 (CRIF1) is an essential mitoribosomal protein for the intramitochondrial production of mtDNA-encoded OXPHOS subunits. Deficiency of CRIF1 impairs the proper formation of the OXPHOS complex, resulting in reduced function. To determine which secretory factors are induced in response to reduced mitochondrial OXPHOS function, we analyzed gene expression datasets inCrif1-depleted mouse embryonic fibroblasts.Crif1deficiency preferentially increased the expression of angiopoietin-like 6 (Angptl6) and did not affect other members of the ANGPTL family. Moreover, treatment with mitochondrial OXPHOS inhibitors increased the expression ofAngptl6in cultured adipocytes. To confirmAngptl6inductionin vivo, we generated a murine model of reduced mitochondrial OXPHOS function using adipose tissue-specificCrif1-deficient mice and verified the upregulation ofAngptl6and fibroblast growth factor 21 (Fgf21) in white adipose tissue. Treatment with recombinant ANGPTL6 protein increased oxygen consumption andPparαexpression through the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway in cultured adipocytes. Furthermore, the ANGPTL6-mediated increase inPparαexpression resulted in increased FGF21 expression, thereby promoting β-oxidation. In conclusion, mitochondrial OXPHOS function governs the expression of ANGPTL6, which is an essential factor for FGF21 production in adipose tissue and cultured adipocytes.
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.|Department of Medical ScienceChungnam National University School of Medicine, Daejeon, Korea.
Seul Gi
SG
Kang
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Hyon-Seung
HS
Yi
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.|Department of Medical ScienceChungnam National University School of Medicine, Daejeon, Korea.
Min Jeong
MJ
Choi
PeptronInc., Daejeon, Korea.
Min Jeong
MJ
Ryu
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Saetbyel
S
Jung
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Hyo Kyun
HK
Chung
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.|Department of Medical ScienceChungnam National University School of Medicine, Daejeon, Korea.
Joon Young
JY
Chang
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Yong Kyung
YK
Kim
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.|Department of Medical ScienceChungnam National University School of Medicine, Daejeon, Korea.
Seong Eun
SE
Lee
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.|Department of Medical ScienceChungnam National University School of Medicine, Daejeon, Korea.
Hyeon-Woo
HW
Kim
Department of BiochemistryChungnam National University School of Medicine, Daejeon, Korea.
Hoil
H
Choi
Department of BiochemistryChungnam National University School of Medicine, Daejeon, Korea.
Dong Seok
DS
Kim
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Ju Hee
JH
Lee
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Koon Soon
KS
Kim
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea.
Hyun Jin
HJ
Kim
Animal Model CenterKorea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
Chul-Ho
CH
Lee
Department of Molecular GeneticsGraduate School of Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Yuichi
Y
Oike
Research Center for Endocrine and Metabolic DiseasesChungnam National University School of Medicine, Daejeon, Korea minhos@cnu.ac.kr.
Minho
M
Shong
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000091308:Angiopoietin-Like Protein 6; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology
D000091308:Angiopoietin-Like Protein 6; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C477602:Angptl6 protein, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
Angptl6; Crif1; mitochondria; oxidative phosphorylation