Avatars of adipose tissue: the saga of transformation of white fat, the villain into brown fat, the protector. Focus on "Inflammation induced by RAW macrophages suppresses the UCP1 mRNA induction via ERK activation in 10T1/2 adipocytes".

THE WORD “AVATAR” (ævətar) is derived from the Sanskrit root word “avata ra,” which means “incarnation,” “manifestation,” “embodiment,” or “transformation” of someone in a different shape or form. Adipose tissue is a depot of fat (triglycerides) that serves as the body’s energy reserves in addition to functioning as an endocrine organ that synthesizes and secretes important metabolic regulatory molecules including hormones and adipokines (9, 16). Adipose tissue in mammals is present mainly in two forms (avatars): 1) white adipose tissue (WAT) and 2) brown adipose tissue (BAT). Obesity caused by excess WAT is associated with insulin resistance, diabetes, cardiovascular risk, and other metabolic syndromes (8). Hence, WAT is considered as the bad avatar of the adipose tissue. On the other hand, BAT utilizes stored fat as the substrate to generate energy (heat) for protection against hypothermia (adaptive thermogenesis), through the uncoupling of oxidative phosphorylation by the uncoupling protein-1 (UCP-1), and thereby, compromising ATP production in mitochondria (12). In human adults, a significant abundance of adipocytes expressing UCP-1, especially in the supraclavicular and neck areas, has been observed (5, 17). These UCP-1-expressing adipocytes are considered to be “brown-like adipocytes” (BLAs), a feature of the BAT avatar. The BLAs emerging from the WAT boost the norepinephrine-induced oxygen consumption and improve insulin sensitivity and are more abundant in mice resistant to obesity (1, 3, 7, 11, 15). Moreover, the actions of BAT are associated with marked suppression of weight gain, control of body weight, a healthy phenotype, and regulation of glucose and fat metabolism. By contrast, a lack of the BAT activity leads to obesity and metabolic disorders. Therefore, BAT is regarded as the good avatar of adipose tissue. The BLAs emerge from the WAT upon certain physiological stimuli and pharmacological treatments (2, 4, 6, 10). It is crucial to identify precisely the physiological cues/factors that are responsible for the transformation (in this context equated with transdifferentiation) of WAT into BLAs in vivo. Currently, there are certain constraints in demonstrating and establishing the expression of UCP-1 as the marker of transformation of WAT into BLAs (the BAT avatar) in experimental animal models because of the complexity of factors that induce UCP-1 in vivo. To overcome those constraints encountered in the in vivo models, in this issue of American Journal of Physiology-Cell Physiology, Sakamoto et al. (13) have conducted an ingenious study by utilizing an in vitro coculture cellular model, consisting of RAW macrophages and C3H10T1/2 adipocytes, to identify the molecular and trans-cellular regulation of UCP-1 expression in adipocytes (WAT surrogate) as a marker of BLAs. The authors show that epinephrine, acting via -adrenergic receptors, cAMP, protein kinase A, and nuclear signaling, induces the expression of UCP-1 mRNA in adipocytes. Furthermore, the authors demonstrate that lipopolysaccharide (LPS)-challenged macrophage conditioned medium and tumor necrosis factor(TNF) suppress the induction of UCP-1 mRNA in adipocytes through extracellular signal-regulated kinase (ERK) activation and subsequent blockade of the nuclear signaling. The study by Sakamoto et al. (13) clearly reveals the -adrenergic stimulation and macrophageand TNF-promoted suppression of UCP-1 mRNA expression in white adipocytes, suggesting that the -adrenergic pathway induces and the activated macrophages (by LPS) and TNFsuppress the transformation of white adipocytes into BLAs (the BAT avatar), and implying that inflammation suppresses the emergence of BLAs from white adipocytes. However, the study by Sakamoto et al. (13) has not (as the authors note) unequivocally demonstrated the induction of