C1q/TNF-related protein 1 (CTRP1) is a conserved plasma protein of the C1q family with notable metabolic and cardiovascular functions. We previously showed that CTRP1 infusion lowers blood glucose and that transgenic mice with elevated circulating CTRP1 are protected from diet-induced obesity and insulin resistance. Here, we use a genetic loss-of-function mouse model to address the requirement of CTRP1 for metabolic homeostasis. Despite similar body weight, food intake, and energy expenditure, Ctrp1 knockout (KO) mice fed a low-fat diet (LFD) developed insulin resistance and hepatic steatosis. Impaired glucose metabolism in Ctrp1-KO mice was associated with increased hepatic gluconeogenic gene expression and decreased skeletal muscle glucose transporter GLUT4 levels and AMPK activation. Loss of CTRP1 enhanced clearance of orally-administered lipids but did not affect intestinal lipid absorption, hepatic VLDL-triglyceride export, or lipoprotein lipase activity. In contrast to triglycerides, hepatic cholesterol levels were reduced in Ctrp1-KO mice, paralleling the reduced expression of cholesterol synthesis genes. Contrary to expectations, when challenged with a high-fat diet (HFD) to induce obesity, Ctrp1-KO mice had increased physical activity and reduced body weight, adiposity, and expression of lipid synthesis and fibrotic genes in adipose tissue; these phenotypes were linked to elevated FGF-21 levels. Due in part to increased hepatic AMPK activation and reduced expression of lipid synthesis genes, Ctrp1-KO mice fed a HFD also had reduced liver and serum triglyceride and cholesterol levels. Together, these results provide genetic evidence to establish the significance of CTRP1 to systemic energy metabolism in different metabolic and dietary contexts.