ANGPTL6 expression is coupled with mitochondria! OXPHOS function to regulate adipose FGF21

Recent studies revealed that the inhibition of mitochondria' oxidative phosphorylation (OXPHOS) is coupled with the mitochondria' 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 mitochondria' OXPHOS function, we analyzed gene expression datasets in Crif1-depleted mouse embryonic fibroblasts. Crif1 deficiency preferentially increased the expression of angiopoietin-like 6 (AngptI6) and did not affect other members of the ANGPTL family. Moreover, treatment with mitochondria' OXPHOS inhibitors increased the expression of AngptI6 in cultured adipocytes. To confirm AngptI6 induction in vivo, we generated a murine model of reduced mitochondria' OXPHOS function using adipose tissue-specific Crif1-deficient mice and verified the upregulation of Angpt16 and fibroblast growth factor 21 (Fgf21) in white adipose tissue. Treatment with recombinant ANGPTL6 protein increased oxygen consumption and Ppara expression through the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway in cultured adipocytes. Furthermore, the ANGPTL6-mediated increase in Ppara expression resulted in increased FGF21 expression, thereby promoting beta-oxidation. In conclusion, mitochondria' OXPHOS function governs the expression of ANGPTL6, which is an essential factor for FGF21 production in adipose tissue and cultured adipocytes.