Targeting adipose tissue

WAT is the largest lipid and energy storage in the human body. Excessive body fat, however, leads to insulin resistance, dyslipidaemia and type 2 diabetes. Over a long time it was believed that WAT is hormonally inert, but this paradigm is now obsolete. Today it is estimated, that the adipose organ is the largest endocrine organ of the human body [1]. Adipose tissue mainly produces and secretes cytokines such as adiponectin (encoded by the murine gene Adipoq), leptin (encoded by the murine gene Lep), resistin, tumor necrosis factor α (TNFα) and interleukins (ILs), which are referred to as adipokines according to their site of secretion [2]. In healthy (lean) subjects, adiponectin has a positive insulin sensitizing effect on other tissues [3]. Leptin is secreted by adipocytes and suppresses appetite by binding to leptin receptors in the central nervous system (CNS) [4]. In obesity, however, different adipokines take over control. Among others, resistin, IL-1, IL-6, and TNFα are secreted from adipocytes, fibroblasts, macrophages and monocytes which reside in adipose tissue. These adipokines are described to be involved in mediating insulin resistance in peripheral tissues and to increase the risk for type 2 diabetes [5-8]. Excess adiposity is not only associated with a dysregulation in adipokine profile, but also with an increased portal release of free fatty acids (FFA). The high concentrations of FFA decrease the hepatic degradation of apolipoprotein B and insulin, which may contribute to the dyslipidemia, hyperinsulinemia, and insulin resistance observed in visceral obesity [9].A current pharmacological approach to counteract insulin resistance and type 2 diabetes is the use of thiazolidinediones (TZDs), which are agonists on peroxisome proliferator-activated receptor γ (PPARγ). TZDs promote differentiation of preadipocytes into white adipocytes [10] and are assumed to redirect FFA away from skeletal muscle towards adipose tissue (the so-called lipid steal hypothes