Loss of APOO (MIC26) aggravates obesity-related whitening of brown adipose tissue via PPARα-mediated functional interplay between mitochondria and peroxisomes

Abstract

Background: Mitochondrial dysfunction and aberrant structure in adipose tissue occur in obesity and obesity-linked brown adipose tissue (BAT) whitening; however, whether this aberrant architecture contributes to or is the result of obesity is unknown. Apolipoprotein O (APOO) is a constitutive protein of the mitochondrial cristae organizing system complex. This study aimed to characterize the physiological consequences of APOO deficiency in vivo.

Methods: APOO expression was analyzed in different human and murine adipose depots, and mice lacking APOO in adipocytes (Apoo^ACKO) are developed to examine the metabolic consequences of adipocyte-specific APOO ablation in vitro and in vivo.

Results: Results showed that APOO expression is reduced in BAT from both diet-induced and leptin-deficient obese mice. APOO-knockout mice showed increased adiposity, BAT dysfunction and whitening, reduced non-shivering thermogenesis, and blunted responses to cold stimuli. APOO deficiency disrupted mitochondrial structure in brown adipocytes and impaired oxidative phosphorylation, thereby inducing a shift from oxidative to glycolytic metabolism, increasing lipogenic enzyme levels and BAT whitening. APOO inactivation inhibited thermogenesis in BAT by reducing mitochondrial long-chain fatty acid oxidation. It also disturbed peroxisomal biogenesis and very long-chain fatty acid oxidation via peroxisome proliferator-activated receptor α.

Conclusions: Altogether, APOO deficiency in adipocytes aggravates BAT whitening and diet-induced obesity; thus, APOO could be a therapeutic target for obesity.

Keywords: APOO; BAT whitening; Brown adipose tissue; Fatty acid oxidation; Obesity.