# Dysfunction of Autophagy in Adipose Tissue Macrophages Regulated via FoxO1 in Obesity-Related Severe Acute Pancreatitis

## TL;DR

Obesity worsens pancreatitis by impairing autophagy in fat tissue macrophages, which is regulated by the FoxO1 protein.

## Contribution

This study identifies FoxO1 and autophagosome-located SNARE proteins as regulators of autophagy in adipose tissue macrophages during obesity-related pancreatitis.

## Key findings

- Obesity worsens inflammation in pancreatitis by impairing autophagy in adipose tissue macrophages.
- FoxO1 regulates autophagosome–lysosome fusion via SNARE proteins in these macrophages.
- Reduced FoxO1 activity exacerbates autophagy impairment and inflammation in obese mice with pancreatitis.

## Abstract

Adipose tissue macrophages (ATMs) play important roles in the progression of obesity-related severe acute pancreatitis (SAP). This study aimed to investigate the alterations of autophagic flux within ATMs, as well as the possible regulatory mechanisms. Obese mice were induced via high-fat diets. SAP was triggered using caerulein and lipopolysaccharide. Inflammatory injuries within pancreatic and adipose tissue were assessed. Autophagic flux, along with the expression of autophagosome-located soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, were examined in ATMs. RNA-sequencing was performed to identify the possible regulatory factor, which was further validated. The results showed that obesity exacerbated inflammatory injuries. ATMs in obesity-related SAP exhibited impaired autophagic flux characterized by reduced autophagosome–lysosome fusion. Expression of autophagosome-located SNARE proteins decreased in ATMs. RNA-sequencing identified Forkhead box as the differentially expressed transcription factor associated with autophagy. The expression and transcriptional activity of Forkhead box O1 (FoxO1) decreased. The inhibition of FoxO1 exacerbated SNARE proteins’ suppression and autophagic flux impairment, while the activation of FoxO1 showed the opposite effect. In conclusion, obesity-induced impaired autophagic flux and autophagosome–lysosome fusion in ATMs are potentially regulated via autophagosome-located SNARE proteins and the transcription factor FoxO1. The impaired autophagic flux in ATMs aggravated inflammatory injuries of obesity-related SAP.