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

TL;DR

Aurantio-obtusin (AO) helps reduce obesity and liver inflammation by repairing mitochondrial damage in brown fat tissue and preventing harmful signals from reaching the liver.

Contribution

AO is shown to reverse mitochondrial damage in brown adipose tissue and block mtDNA transfer to the liver, offering a novel therapeutic strategy for obesity-related inflammation.

Findings

AO improves mitochondrial metabolism in brown adipose tissue and reduces hepatic inflammation in obese mice.

AO prevents mtDNA release and EV-mediated STING activation, protecting against liver inflammation.

BAT transplants from AO-treated mice protect recipient mice from hepatic inflammation.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13020-025-01097-y.

Figures