CTRP2 is a secreted plasma protein of the C1q family that enhances glycogen deposition and fat oxidation in cultured myotubes. Its in vivo metabolic function, however, has not been established. We show here that acute and chronic metabolic perturbations induced by fasting or high-fat feeding up-regulated the mRNA expression of Ctrp2 in white adipose tissue without affecting its circulating plasma levels. We generated a transgenic mouse model with elevated circulating levels of CTRP2 to determine its metabolic function in vivo. When fed a low-fat diet, wild-type and CTRP2 transgenic mice exhibited no metabolic phenotypes. When challenged with a high-fat diet to induce obesity, wild-type and CTRP2 transgenic mice had similar weight gain, adiposity, food intake, metabolic rate, and energy expenditure. Fasting serum lipid and adipokine profiles were also similar between the two groups of mice. However, while glucose and insulin levels in the fasted state were comparable between wild-type and CTRP2 transgenic mice, insulin levels in the fed state were consistently lower in transgenic mice. Notably, CTRP2 transgenic mice had improved insulin tolerance and a greater capacity to handle acute lipid challenge relative to littermate controls. Our results highlight, for the first time, the in vivo role of CTRP2 in modulating whole-body metabolism.