Using bioinformatics techniques and sequence analyses algorithms, we identified that tumor necrosis factor-α (TNF-α) and nitric oxide (NO) have a significant role in the pathobiology of insulin resistance syndrome, a condition that is common in subjects with abdominal obesity, hypertension, dyslipidemia, atherosclerosis, and coronary heart disease and are accompanied by endothelial dysfunction due to reduced endothelial nitric oxide generation. TNF-α has neurotoxic actions, stimulates inducible NO synthase activity, and modulates the expression of neurotransmitters involved in the control of feeding and thermogenesis. NO is a neurotransmitter and influences secretion and actions of various hypothalamic peptides and neuropeptides. Insulin suppresses the production of TNF-α but stimulates that of endothelial NO. This close interaction between TNF-α, NO, hypothalamic peptides, and insulin suggests that regulation of TNF-α and NO production and action could be critical in the management of insulin resistance syndrome and its associated conditions.