Obesity has progressively developed over time if there is imbalance in energy homeostasis. The World Health Organization has listed obesity as one of the significant health problems in westernized societies. Obesity has the association with various chronic diseases such as non-insulin-dependent diabetes (type 2 diabetes), hypertension, dyslipidemia, cardiovascular disease, and cancer. These medical problems are collectively referred to as the metabolic syndrome or Syndrome X. The common feature of the syndrome is the decrease in sensitivity of the body to the actions of insulin that regulates metabolism of glucose and lipids, a condition termed as insulin resistance. A long term objective of our laboratory is to identify the mechanism by which insulin resistance is developed, and to identify the regulatory programs that overcome the insulin resistance. Nuclear receptors function as ligand-activated transcription factors that regulate the e-x-p-r-e-s-s-i-o-n of target genes. The superfamily of these nuclear receptors includes traditional endocrine receptors for steroids, thyroid hormones, vitamin D3, and retinoids, as well as a large number of orphan receptors of which ligands and physiological functions are initially unknown. Peroxisome proliferator-activated receptor γ (PPARγ), the most intensively studied and well characterized nuclear receptor in lipid homeostasis and insulin sensitivity, has been known as an ultimate effector of adipogenesis and dominant-negative mutations in a single allele PPARG (the gene encoding PPARγ) have been resulted in lipoatrophy and insulin. Furthermore, thiazolidinedione, PPARγ agonist, has been used as an insulin-sensitizer to stimulate muscle glucose disposal and inhibit hepatic glucose production in insulin-resistant animal models and patients. TR4, a member of the nuclear receptor superfamily, is able to regulate the e-x-p-r-e-s-s-i-o-n of target genes through binding to direct repeat AGGTCA core motif sequences with variable numbers of spacer nucleotides. Many nuclear receptors including PPARs, liver X receptor and retinoid X receptor involved in adipogenesis and lipid homeostasis have shown to regulate e-x-p-r-e-s-s-i-o-n of target genes via these elements, suggesting that TR4 may be involved in these processes. TR4 is expressed in the liver, skeletal muscle and adipose tissues important for lipid metabolism and insulin sensitivity. The results of our preliminary studies indicated that TR4-/- mice exhibited reduced fat accumulation with increased insulin sensitivity. Therefore, Defining the role of TR4 is of considerable physiological importance. My recent research has focused on the mechanism by which ablation of TR4 causes altered e-x-p-r-e-s-s-i-o-n of genes involved in lipid homeostasis. We are also testing if these alterations are of which functional consequence in adiposity and insulin sensitivity. The success of these investigations will provide us to develop novel drug therapies or other medical interventions to improve insulin sensitivity in diabetes care.