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ANGPTL6 expression is coupled with mitochondrial OXPHOS function to regulate adipose FGF21
- Source :
- Journal of Endocrinology. 233:105-118
- Publication Year :
- 2017
- Publisher :
- Bioscientifica, 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 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 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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
FGF21
Endocrinology, Diabetes and Metabolism
Adipose tissue
Mice, Transgenic
Oxidative phosphorylation
White adipose tissue
Mitochondrion
Oxidative Phosphorylation
Mice
03 medical and health sciences
Oxygen Consumption
Endocrinology
Downregulation and upregulation
3T3-L1 Cells
Internal medicine
Mitochondrial unfolded protein response
Adipocytes
medicine
Animals
Angiopoietin-Like Protein 6
Protein kinase A
Chemistry
Fibroblasts
Mitochondria
Fibroblast Growth Factors
Angiopoietin-like Proteins
030104 developmental biology
Adipose Tissue
Hepatocytes
Angiopoietins
Subjects
Details
- ISSN :
- 14796805 and 00220795
- Volume :
- 233
- Database :
- OpenAIRE
- Journal :
- Journal of Endocrinology
- Accession number :
- edsair.doi.dedup.....51cbe823c452e605dc278641cc1bcfc6