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

Area of Science:

• Cell Biology
• Metabolic Regulation
• Mitochondrial Function

Background:

• Inhibition of mitochondrial oxidative phosphorylation (OXPHOS) links to the unfolded protein response, releasing factors that influence systemic energy metabolism.
• The specific non-cell autonomous factors secreted by adipose tissue due to impaired OXPHOS are not well-defined in mammals.

Purpose of the Study:

• To identify secretory factors induced by reduced mitochondrial OXPHOS function in adipose tissue.
• To investigate the role of CR6-interacting factor 1 (CRIF1) deficiency in regulating these factors.
• To elucidate the signaling pathway involving ANGPTL6 and FGF21 in response to mitochondrial dysfunction.

Main Methods:

• Analysis of gene expression datasets from Crif1-depleted mouse embryonic fibroblasts.
• Treatment of cultured adipocytes with OXPHOS inhibitors and recombinant ANGPTL6 protein.
• Generation of adipose tissue-specific Crif1-deficient mice to study in vivo effects.
• Assessment of oxygen consumption, gene expression (Angptl6, Fgf21, Pparα), and signaling pathways (ERK/MAPK).

Main Results:

• CRIF1 deficiency preferentially upregulated angiopoietin-like 6 (ANGPTL6) expression.
• Reduced OXPHOS function in vivo induced ANGPTL6 and fibroblast growth factor 21 (FGF21) in white adipose tissue.
• ANGPTL6 treatment stimulated oxygen consumption and PPARα expression via ERK/MAPK signaling.
• ANGPTL6-induced PPARα upregulated FGF21, promoting fatty acid beta-oxidation.

Conclusions:

• Mitochondrial OXPHOS function directly regulates ANGPTL6 expression in adipose tissue.
• ANGPTL6 acts as a key mediator for FGF21 production in response to mitochondrial dysfunction.
• This pathway highlights a novel mechanism linking mitochondrial health to systemic energy homeostasis via adipose-derived factors.