Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue

Abstract

Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes.

Keywords: adipose tissue; endoplasmic reticulum stress; inflammation; metabolic disorder; obesity.

Figure 1

Mechanism of ERS and unfolded protein response: Under ERS, UPR is activated, causing the activation of three downstream branches, PERK, IRE1 and ATF6, and stimulating genes and transcription factors related to protein folding and ERAD.

Figure 2

ERS regulates adipogenesis: The overactivation of ERS in adipose tissue causes downstream UPR to regulate adipogenesis. IRE1 stimulates CCAAT/enhancer binding protein-A (C/EBPa) to promote lipogenesis and related transcription factors via XBP1s. PERK and ATF6 regulate lipogenesis by 1/Sterol regulatory element binding protein 1 (SREBP-1).

Figure 3

ERS-induced inflammatory cascade: PERK, IRE1 and ATF6 activate the inflammatory pathway with NF-κB, JNK and IKK as the core through the downstream branches, respectively. PERK directly activates NF-κB via NRF2 and also mediates Akt activation of autophagy and associated inflammatory transcription factors. IRE1 mainly mediates downstream inflammatory pathways through the IRE1-TRAF2 axis, and can also lead to apoptosis through Bcl2. ATF6 can induce autophagy through active forms and regulate inflammatory responses through the NF-κB pathway.