Impaired Autophagic Flux in Adipose Tissue Aggravates Pancreatic Injury in Obesity-Related Severe Acute Pancreatitis.

Abstract

BACKGROUND: Adipose tissue (AT) playing a crucial role in obesity-related pancreatitis. This study investigated the impact of autophagy in AT on pancreatic injury during obesity-related severe acute pancreatitis (SAP). METHODS: Non-obese and obese mice were induced using a normal diet (ND) or high-fat diet (HFD) before establishing SAP. Pancreatic injury and autophagy in AT were evaluated. Adipose tissue macrophages (ATMs) were analyzed. Autophagy in RAW 264.7 cells co-cultured with palmitic acid (PA) and lipopolysaccharide (LPS), simulating the conditions of ATMs during SAP, was further investigated. The effect of PA on autophagy within inflammatory macrophages in vitro was explored, utilizing Sulfo-N-succinimidyloleate (SSO) to inhibit fatty acid transport. Additionally, the impact of autophagy in AT on inflammation in SAP mice was investigated using SSO, complemented by metabolomics analysis to uncover underlying molecular mechanisms. RESULTS: Pancreatic histological scores were significantly higher in obese SAP mice than in non‑obese SAP mice (n = 6; 9.50 ± 1.05 vs. 7.33 ± 1.03; p = 0.0005). Impaired autophagic flux was observed in the AT of obese SAP mice compared with obese control mice, as indicated by increased LC3‑II (p = 0.0383) and p62 levels (p = 0.0171). PA induced impaired autophagic flux in inflammatory macrophages. Inhibition of fatty acid transport partially restored impaired autophagic flux in an ATM cell model of SAP. Furthermore, this inhibition also alleviated the impairment of autophagic flux in AT and attenuated pancreatic injury in obese SAP mice. Metabolomics analysis of AT revealed elevated levels of more fatty acids and several signaling pathways correlated with autophagy in obese SAP mice. CONCLUSION: Impaired autophagic flux in AT aggravates pancreatic injury in obese SAP mice, with impaired autophagic flux in ATMs likely playing a crucial role. Metabolomics analysis revealed abnormal lipid metabolism in AT of obese SAP mice, and several signaling pathways may contribute to impaired autophagic flux in this tissue.