Plin5 alleviates endoplasmic reticulum stress to promote white adipose tissue remodeling

Obesity is characterized by impaired white adipose tissue (WAT) remodeling, dysregulated lipid metabolism, and chronic endoplasmic reticulum (ER) stress. Perilipin 5 (Plin5), a lipid droplet-associated protein, has been implicated in lipid metabolism and ER homeostasis, but its role in WAT remodeling remains poorly understood. This study investigated whether Plin5 regulates adipose tissue remodeling through modulation of ER stress and whether Plin5 contributes to the metabolic effects of Tirzepatide. Adipose-specific Plin5 overexpression was achieved in db/db mice using adeno-associated virus (AAV), and metabolic phenotypes, lipid metabolism, and ER stress were evaluated. Gain- and loss-of-function studies were performed in cultured adipocytes. Candidate Plin5-interacting proteins were identified by co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) and validated by co-immunoprecipitation. ER stress was pharmacologically inhibited using 4-phenylbutyric acid (4-PBA). The effects of Tirzepatide on Plin5 expression and adipocyte metabolism were further investigated in vivo and in vitro. Adipose-specific Plin5 overexpression reduced body weight, adipocyte hypertrophy, lipid accumulation, and lipogenic protein expression while promoting lipolysis in db/db mice, and similar effects were observed in cultured adipocytes. Plin5 overexpression attenuated ER stress, whereas Plin5 knockdown aggravated ER stress and lipid accumulation. Mechanistically, WFS1 was identified as a Plin5-interacting protein, and Plin5 enhanced WFS1 protein stability by reducing its ubiquitination. Pharmacological inhibition of ER stress with 4-PBA largely recapitulated the lipid-lowering effects of Plin5. In addition, Tirzepatide restored Plin5 expression in WAT, and Plin5 knockdown attenuated the beneficial effects of Tirzepatide on lipid metabolism and ER stress in adipocytes. Plin5 contributes to white adipose tissue remodeling by alleviating ER stress and regulating lipid homeostasis, potentially through stabilization of WFS1. In addition, Plin5 contributes to the metabolic effects of Tirzepatide in adipose tissue. These findings provide mechanistic insight into the role of Plin5 in adipose tissue remodeling and suggest that the Plin5-WFS1 pathway may represent a potential therapeutic target for obesity and related metabolic disorders.