TRIM65 deficiency exacerbates HFD-induced obesity in mice associated with elevated adipose tissue inflammation and lipid accumulation.

Abstract

Obesity is linked to metabolic and cardiovascular complications, such as atherosclerosis, type 2 diabetes (T2DM), and hypertension. Despite current therapies alleviate certain clinical manifestations, effective disease-modifying targets remain scarce. TRIM65 (tripartite motif-containing 65) has been linked to carcinogenesis, immune modulation, and inflammatory responses, yet its role in obesity remains unknown. Here, we aimed to elucidate the pathophysiological function of TRIM65 in obesity and to reveal the molecular networks regulating this process. Our results demonstrated a significant decrease in TRIM65 expression under obese conditions. Notably, TRIM65 knockout mice exhibited exacerbated high fat diet (HFD)-induced obesity, as evidenced by marked increases in body and white adipose tissue (WAT) weight, enlarged adipocyte sizes, elevated systemic and tissue inflammation, and impaired glucose and insulin tolerance. Furthermore, knockout of TRIM65 aggravated HFD-induced dyslipidemia, hepatic steatosis, and liver injury. Mechanistically, TRIM65 deficiency triggered the ERK1/2-NF-κB signaling cascade, leading to a pro-inflammatory environment and aggravating insulin resistance. Simultaneously, TRIM65 deficiency enhanced the expression of adipogenic and lipogenic genes while diminishing that of lipolytic genes, culminating in increased lipid accumulation. Collectively, TRIM65 is established by our findings as a pivotal negative regulator that coordinately curbs lipid synthesis and inflammatory responses, thereby positioning it as an attractive therapeutic target for obesity and its metabolic complications.