The deficiency of Usf1 confers a remarkable number of clinically relevant beneficial metabolic effects in mice via activation of brown adipose tissue. The Usf1 deficient mice have high serum HDL-cholesterol and low triglyceride levels, a beneficial lipid profile opposite to that of human metabolic syndrome. The elevated HDL-C is associated with enhanced cholesterol efflux, and low triglycerides with decreased hepatic VLDL production and elevated triglyceride clearance. Despite their elevated food intake and lower physical activity, the Usf1 deficient mice are protected against diet-induced obesity. Their concomitant increase in energy expenditure is related to the activation of brown adipose tissue. The protective effects of Usf1 deficiency against obesity, insulin resistance, fatty liver, dyslipidemia, vascular inflammation, and atherosclerosis coupled with brown adipose tissue activation are demonstrated. Inhibition or silencing of USF1 is suggested as a therapeutic target to treat various human diseases.