Aurantio-obtusin improves obesity and protects hepatic inflammation by rescuing mitochondrial damage in overwhelmed brown adipose tissue

Abstract

Background

Obesity is frequently linked to chronic systamic inflammation and presents significant challenges to public health. Aurantio-obtusin (AO) boosted the brown adipose tissue (BAT) thermogenesis in diet-induced obesity. However, the specific mechanisms by which injured mitochondria-related damage signals derived from overwhelmed BAT can transmit to liver and exacerbate metabolic disorders and whether AO can reverse this process remain unknown.

Materials and methods

After applying high-fat diet and glucose-fructose water (HFHS)-induced obesity mice, different BAT transplant procedures and primary BAT adipocytes, we investigated the anti-obesity effects and mechanism of AO through RNA sequencing and biology techniques.

Results

AO improved whole-body lipid accumulation, mitochondrial metabolism in BAT and hepatic inflammation in HFHS-induced obesity mice. Interscapular transplant of BAT-derived from obese donor mice triggered hepatic inflammation of chow diet-fed recipient mice, which was protected by AO. Furthermore, the transplantation of BAT-derived from AO-treated mice protected hepatic inflammation in obese mice. In vivo and in lipid-challenged primary BAT adipocytes, AO decreased kexin type 9 (PCSK9), prevented mPTP opening and mitochondrial DNA (mtDNA) release in extracellular vesicles (EVs) manner by inhibiting the acetylation of cyclophilin D associated with adenine nucleotide translocase, suppressing oligomerization of voltage-dependent anion channel 1 and activating mitophagy. Ultimately, AO inhibited mtDNA-containing EVs-induced cyclic GMP-AMP synthase/stimulator of interferon genes (STING) activation and hepatic inflammation, which was confirmed by Sting^−/− mice.

Conclusion

AO not only improves thermogenesis and mitochondrial function of BAT but also prevents liver inflammation by repairing mitochondrial function and blocking the transfer of mtDNA from BAT to the liver.

Graphic abstract