Abstract Abdominal obesity is tightly associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. Visceral adipose tissues, especially mesenteric adipose tissue, exhibit depot-specific immune and metabolic differences compared with subcutaneous adipose tissue and has been linked to varying degrees of metabolic diseases. Adiponectin is an adipokine that possesses anti- diet-induced inflammation and insulin resistance functions. While the beneficial role of adiponectin is largely explored in subcutaneous adipose tissue, the role of adiponectin in controlling peritoneal cavity organ inflammation and mesenteric adipose tissue expansion remains largely unclear. The proposed study aims at elucidating the role of adiponectin signaling in regulating macrophage function and metabolic homeostasis, focusing on a new target of the adiponectin signaling pathway, the abhydrolase domain containing 17B depalmitoylase (ABHD17B). The premise of the current study is based on several key findings made in our preliminary studies: 1) the Abhd17b gene is selectively expressed in macrophage; its expression is greatly reduced in adiponectinKO mice or high fat diet-fed mice; 2) Abhd17b deficiency exacerbates diet-induced abdominal obesity, visceral organ inflammation, insulin resistance, and mesenteric adipose tissue expansion; 3) Abhd17b deficient macrophage displayed impaired phagocytic ability and augmented inflammation. These data suggest the role of ABHD17B in mediating the anti-inflammatory function of adiponectin in macrophage. Our overarching hypothesis is that ABHD17B downregulation-induced macrophage dysfunction may be a key mechanism underlying adiponectin deficiency-induced metabolic impairment in obesity. The studies described in this proposal will test this hypothesis by characterizing the physiological roles of ABHD17B in mediating adiponectin function and by characterizing the mechanism by which ABHD17B mediates the beneficial effects of adiponectin on phagocytosis and anti-inflammation. Our multidisciplinary team of scientists will use genetic mouse models and biochemical and cell-based assays to dissect the function and mechanism of ABHD17B in regulating adiponectin signaling. Given the vast impact of abdominal obesity on human health, this proposed work offers a unique and innovative approach to interrogate the functional roles and regulation of a new target of adiponectin, ABHD17B, in mediating the anti-inflammation and anti-insulin resistant roles of adiponectin. The mechanistical studies will help to develop new therapeutic treatment of abdominal obesity related metabolic diseases including type 2 diabetes.