The effects of caloric restriction on Fetuin-A and cardiovascular risk factors in rats and humans: a randomized controlled trial

Summary Objectives The liver‐secreted protein fetuin‐A is associated with insulin resistance, metabolic syndrome, type 2 diabetes and atherosclerosis. We examined the effect of caloric restriction (CR) on fetuin‐A levels and concomitant changes in hepatic steatosis and cardiovascular risk factors in rats and humans. Design and Subjects We performed a randomized, controlled clinical trial to examine circulating fetuin‐A levels and cardiovascular risk parameters including visceral fat area (VFA), atherogenic lipid profile, inflammatory markers, adipokines levels and brachial artery endothelial function in 76 overweight women with type 2 diabetes before and after 12 weeks of CR. In addition, the effects of CR on hepatic steatosis and fetuin‐A mRNA expression were evaluated in Otuska Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and type 2 diabetes. Results Circulating fetuin‐A levels were significantly decreased after 12 weeks of CR and were accompanied by improvements in VFA, blood pressure, glucose, lipid profiles and liver function. The CR group also showed a significant decrease in apolipoprotein B, leptin and insulin resistance compared to those in the control group, although endothelial function was not different. Multiple regression analysis showed that the changes in fetuin‐A levels were independently associated with CR and changes in hsCRP and adiponectin (R2 = 0·156). Moreover, CR significantly reduced hepatic steatosis and fetuin‐A expression, as well as weight, glucose, total cholesterol and triglyceride levels, in OLETF rats. Conclusion Caloric restriction significantly reduced the hepatic expression of fetuin‐A and its circulating levels and improved several cardiovascular risk factors in obese rats and humans with type 2 diabetes.