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

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. APOO expression was analyzed in different human and murine adipose depots, and mice lacking APOO in adipocytes (ApooACKO) are developed to examine the metabolic consequences of adipocyte-specific APOO ablation in vitro and in vivo. 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. Altogether, APOO deficiency in adipocytes aggravates BAT whitening and diet-induced obesity; thus, APOO could be a therapeutic target for obesity. [Display omitted] •APOO deficiency aggravates BAT whitening and impaired non-shivering thermogenesis.•APOO inactivation inhibits thermogenesis in brown adipocytes via a dual role.•APOO inactivation decreases mitochondrial LCFA oxidation by repressing bioenergetic capacity.•APOO inactivation disturbs peroxisomal VLCFA oxidation by destroying the coordination between mitochondria and peroxisome.•Inflammation-induced PPARα inhibition is responsible for reduced peroxisome activity.