ANGPTL6 expression is coupled with mitochondrial OXPHOS function to regulate adipose FGF21

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Title
ANGPTL6 expression is coupled with mitochondrial OXPHOS function to regulate adipose FGF21
Author(s)
S G Kang; H S Yi; M J Choi; M J Ryu; S Jung; H K Chung; J Y Chang; Y K Kim; S E Lee; H W Kim; H Choi; D S Kim; J H Lee; K S Kim; H J Kim; Chul Ho Lee; Y Oike; M Shong
Bibliographic Citation
Journal of Endocrinology, vol. 233, no. 1, pp. 105-118
Publication Year
2017
Abstract
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 noncell 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 mtDNAencoded 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 in Crif1-depleted mouse embryonic fibroblasts. Crif1 deficiency 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 of Angptl6 in cultured adipocytes. To confirm Angptl6 induction in vivo, we generated a murine model of reduced mitochondrial OXPHOS function using adipose tissue-specific Crif1-deficient mice and verified the upregulation of Angptl6 and fibroblast growth factor 21 (Fgf21) in white adipose tissue. Treatment with recombinant ANGPTL6 protein increased oxygen consumption and Pparα expression through the extracellular signal-regulated kinase/ mitogen-activated protein kinase pathway in cultured adipocytes. Furthermore, the ANGPTL6-mediated increase in Pparα expression 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.
Keyword
Angptl6Crif1MitochondriaOxidative phosphorylation
ISSN
0022-0795
Publisher
Bioscientifica Ltd
DOI
http://dx.doi.org/10.1530/JOE-16-0549
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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