Ames dwarf mice are long-lived and insulin sensitive, and have a normal or reduced percentage of body fat. Calorie restriction (CR) is known to improve insulin sensitivity and reduce body fat. The purpose of this study was to evaluate the mechanism of improved insulin sensitivity in the Ames dwarfs and the effects of CR on adipose signaling and metabolism in normal and dwarf mice. Enhanced insulin sensitivity in dwarf mice may be partly due to increased release of adiponectin and the reduced release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Altered levels of adipocytokines might be consequent to the decreased lipid synthesis, plasma triglycerides, and free fatty acid levels. In normal mice, CR improves insulin sensitivity by affecting the release of adipocytokines, and decreasing circulating fatty acid and triglycerides concentrations as well as liver triglyceride accumulation. However, CR may reduce rather than enhance some of the insulin effects in the highly insulin-sensitive dwarf mice.