Previously we have demonstrated that whole body hyperthermia (WBH) improves insulin resistance in diabetic mice. The aim of the present study was to perform a gene expression analysis of the liver and adipose tissue of obesity-induced insulin resistant diabetic mice (db/db mice) after WBH and to define the molecules that play the important role in improvement of insulin resistance by WBH. Male db/db mice were treated with WBH 3 times per week for 12 weeks. Total RNA was extracted from the liver and adipose tissue of db/db mice, and differences in the gene expression profiles among db/+ mice, untreated db/db mice, and WBH-treated db/db mice were investigated using a high-density DNA microarray. WBH directly targets liver and adipose tissue, resulting in modifications in NF-kappaB and IL-6 signalling pathways, as well as lipid metabolism. Although the mechanisms have not yet been completely investigated, we can conclude that WBH may provide a new therapeutic or preventive modality against type 2 diabetes mellitus and metabolic or insulin resistance syndrome through the modification of several signalling pathways.