The role of adipocyte-secreted resistin/adipocyte-specific secretory factor (ADSF)/FIZZ3 in obesity and diabetes has been controversial at best. Recently generated resn knockout mice showed normal glucose and insulin sensitivity with lower fasting glucose levels. Upon feeding with a high-fat diet, the knockout mice exhibited increased glucose tolerance with decreased hepatic glucose output, possibly due to phosphorylation and activation of AMP-activated protein kinase and suppression of gluconeogenic genes. In comparison, transgenic mice overexpressing a dominant negative form of resistin/ADSF/FIZZ3 showed increased adiposity with elevated leptin and adiponectin levels, accompanying enhanced glucose tolerance and insulin sensitivity both on chow and high-fat diets. Although its underlying mechanisms need further elucidation, the in vivo studies demonstrate a role of resistin/ADSF/FIZZ3 in obesity and insulin resistance.