The effects of oral niacin-bound chromium (NBC) supplementation on the subcutaneous fat tissue of type II Lepr^db obese diabetic mice was examined using high density comprehensive mouse genome (45,101 probe sets) expression arrays. The influence of such supplementation on the plasma cardiovascular risk factors of these mice was also investigated. Supplementation of NBC had no significant effect on age-dependent weight gain in the Lepr^db obese diabetic mice. However, NBC lowered total cholesterol (TC), TC:HDL ratio, LDL cholesterol and triglyceride levels while increasing HDL cholesterol in the blood plasma. No effect of NBC supplementation was observed on fasting blood glucose levels. Oral glucose tolerance test revealed a significantly improved clearance of blood glucose between 1h and 2h of glucose challenge in NBC supplemented mice. Unbiased genome-wide interrogation demonstrated that NBC resulted in the up-regulation of muscle-specific gene expression in the fat tissue. Genes encoding proteins involved in glycolysis, muscle contraction, muscle metabolism and muscle development were specifically up-regulated in response to NBC supplementation. Genes in the adipose tissue that were down-regulated in response to NBC supplementation included CIDEA and UCP-1, which represent key components involved in the thermogenic role of brown adipose tissue and TTP, the primary carrier of alpha-tocopherol to adipose tissue. The observation that CIDEA-null mice are resistant to obesity and diabetes suggest that the inhibitory role of NBC on CIDEA expression was favorable. Further studies testing the molecular basis of NBC function and long-term outcomes are warranted.