The present study is the first time to disclose that shed Sdc4 extracellular domain was considerably increased in the serum of HFD-induced obese mice, while this induction was significantly attenuated in adipocyte-Sdc4 deficient mice associating with reduced body weight gain and alleviated metabolic syndrome, including glucose intolerance and steatohepatitis indicating adipocyte is the primary cellular source of shed Sdc4 which plays a novel role in the pathogenesis of obesity and its related metabolic disorders. This evidence concerns the gene SDC4 and metabolic syndrome.