2018-LB: ABHD17B Modulates Diet-Induced Abdominal Obesity and Chronic Inflammation

Overnutrition induces abdominal obesity and chronic inflammation in humans. Despite the central role of hyperactive pro-inflammatory macrophages, the mechanisms underlying macrophage dysregulation due to overnutrition remains poorly understood. Here, we present the first evidence of the physiological role of ABHD17B, a putative depalmitoylase, in rodents through the generation of whole-body knockout mice and macrophage-specifical knockout mice. Our findings identify macrophages as the primary cellular source of ABHD17B and reveal reduced ABHD17B expression in high fat diet-fed mice. ABHD17B deficiency exacerbates diet-induced abdominal obesity, gut dysfunction, insulin resistance, and inflammation in both knockout mouse models. Furthermore, the loss of ABHD17B amplifies macrophage pro-inflammatory responses and compromises phagocytic efficiency. Mechanistically, ABHD17B de-palmitoylates C5aR2, a pro-inflammatory complement C5a receptor, in macrophages. Deletion of the Abhd17b gene in macrophages enhances the receptor expression and plasma membrane location, stimulates ROS production, and potentiates TLR4-mediated pro-inflammatory signaling. Collectively, our study unveils ABHD17B as a novel anti-inflammatory depalmitoylase crucial for maintaining protein palmitoylation homeostasis in macrophages. Additionally, ABHD17B-C5aR2 signaling emerges as a critical player in safeguarding against over-nutrition induced excessive macrophage inflammation and abdominal obesity.