HERP constrains white adipose expansion and inflammation by STEAP4 stabilization.

Obesity is defined as excessive white adipose tissue (WAT) expansion and adipose inflammation. HERP is a crucial member of the ERAD machine and plays a critical role in protein degradation. Nevertheless, its role in adipose tissue remains uncharacterized. Here we identify HERP as a nutrient-sensing factor. When fed a low-fat diet, both male and female HERP-KO mice exhibited adipose expansion and mild metabolic disturbances without altered body weight. Conversely, high-fat diet-fed HERP-KO mice developed exacerbated obesity, adipose expansion, and severe metabolic disorders. Further analysis revealed that HERP deficiency stimulated adipogenesis/lipogenesis and inflammation in WAT and primary adipocytes, driving the observed phenotypes. Intriguingly, chronic HFD exposure induced adipogenic/lipogenic resistance in HERP-deficient WAT. Mechanistically, HERP interacted with STEAP4 to prevent its ubiquitin-mediated degradation. HERP regulates adipogenesis through STEAP4 in a PPARγ-dependent manner. Enhancing STEAP4 expression ameliorated adipose expansion, obesity, and metabolic disorders in HERP-KO mice by suppressing adipogenesis/lipogenesis and inflammation in WAT. Clinically, HERP and STEAP4 expression inversely correlate with BMI, showing reduced levels in overweight individuals. Collectively, our study establishes HERP as a protective factor against adipose expansion and inflammation, revealing potential therapeutic strategies for obesity.