In rat hepatocyte culture, the S14 gene is necessary for induction of lipogenesis by carbohydrate metabolism and thyroid hormone. To determine if this gene plays a role in regulation of lipid storage in humans we compared the response to fasting of the human S14 gene between obese and nonobese subjects. We measured the relative content of human S14 mRNA in abdominal subcutaneous fat before and after a 48-hour fast. We found that mRNA-S14 is strongly downregulated in nonobese subjects in response to the fast, but only minimally down-regulated in obese subjects. There is an excellent correlation between the body mass index, and the fasting induced fall in S14 mRNA. There was no difference in the postfasting glucose, insulin, and ketone levels between the 2 groups of subjects. Therefore, the S14 gene is abnormally downregulated during fasting in adipose tissue of obese individuals. Further study of this gene could provide important information on the mechanism of the acquisition or maintenance of obesity in humans.