Insulin resistance is an underlying cause of type 2 diabetes. Mitochondrial dysfunction characterized by impaired oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism of insulin resistance. However, the cause and initiating organ of OXPHOS dysfunction in the development of systemic insulin resistance has yet to be identified. Chronic inflammation of white adipose tissue (WAT) is a critical process in the development of systemic insulin resistance in excessive adiposity. Furthermore, dysfunction of cellular organelles, including mitochondria and endoplasmic reticulum (ER), is considered to be the underlying cause of insulin resistance and type 2 diabetes. Adipose mitochondrial mass is suppressed in the insulin resistant state and improvement of insulin resistance with a PPARγ agonist is associated with increased adipose mitochondrial biogenesis. These results strongly suggest that the dysregulation of mitochondrial function in adipose tissue plays a critical role in the development of insulin resistance and diabetes. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotypes of mice with OXPHOS-deficient adipose tissue were analyzed. In this symposium, detailed analytical results on systemic insulin resistance will be discussed in mice model of adipose mitochondrial dysfunction. These findings indicate that OXPHOS reserves in adipose tissue determine metabolic and inflammatory responses and can cause systemic inflammation and insulin resistance.