Two Faces of White Adipose Tissue with Heterogeneous Adipogenic Progenitors

Abstract

Chronic energy surplus increases body fat, leading to obesity. Since obesity is closely associated with most metabolic complications, pathophysiological roles of adipose tissue in obesity have been intensively studied. White adipose tissue is largely divided into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). These two white adipose tissues are similar in their appearance and lipid storage functions. Nonetheless, emerging evidence has suggested that SAT and VAT have different characteristics and functional roles in metabolic regulation. It is likely that there are intrinsic differences between VAT and SAT. In diet-induced obese animal models, it has been reported that adipogenic progenitors in VAT rapidly proliferate and differentiate into adipocytes. In obesity, VAT exhibits elevated inflammatory responses, which are less prevalent in SAT. On the other hand, SAT has metabolically beneficial effects. In this review, we introduce recent studies that focus on cellular and molecular components modulating adipogenesis and immune responses in SAT and VAT. Given that these two fat depots show different functions and characteristics depending on the nutritional status, it is feasible to postulate that SAT and VAT have different developmental origins with distinct adipogenic progenitors, which would be a key determining factor for the response and accommodation to metabolic input for energy homeostasis.

Keywords: Adipogenesis; Adipose tissue; Energy metabolism; Inflammation; Obesity; Stem cells.

Fig. 1. Adipose tissue distribution in human and heterogeneous characteristics between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese mice. (A) In human, adipose tissues are found in areas all over the body. In particular, brown adipose tissue is localized in neck, shoulder, and thorax to generate heat via higher activity of mitochondria and uncoupling protein-1 (UCP-1). VAT is localized in intra-abdomen and SAT is spread throughout the whole body. Both SAT and VAT have a higher capacity for lipid storage than brown adipose tissue. (B) In obese mice, SAT and VAT are differentially respond to obesity in many aspects such as immune responses, adipogenesis, and vasculatures. In obese mice, VAT exhibit elevated fibrosis and inflammatory responses accompanied with increased in vivo adipogenic potential. In contrast, such effects were rarely observed in obese SAT. Moreover, prolonged obesity reduces vasculature in obese VAT, whereas vasculature in obese SAT is denser than that in obese VAT.

Fig. 2. Dissimilarity of vascularization and angiogenesis in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) upon high-fat diet (HFD) feeding. Endothelial cells were stained with CD31 antibody conjugated with fluorescein isothiocyanate (FITC) fluorescence. Upon HFD feeding, vascular structures of visceral epididymal adipose tissue (EAT) are dramatically reduced compared to normal chow diet (NCD) fed mice. However, subcutaneous inguinal adipose tissue (IAT) in obesity maintains a similar degree of vasculatures compared to IAT in NCD condition. Scale bar indicates 100 µm.

Fig. 3. Immune cells and pro-inflammatory responses in obesity. Normal and healthy adipose tissue harbors various types of anti-inflammatory immune cells such as M2-like macrophages (M2 MAC), eosinophils, helper T type 2 (T_H2) cells, regulatory T (Treg) cells, and invariant natural killer T (iNKT) cells. These immune cells are involved in maintaining normal adipose functions and insulin sensitivity. In obesity, the number of pro-inflammatory immune cells including neutrophil, M1-like macrophages (M1 MAC), neutrophils, helper T type 1 (T_H1) cells, Cytotoxic T (Tc) cells, and natural killer (NK) cells are elevated. In parallel, anti-inflammatory immune cells are decreased, leading to aggravation of adipose tissue inflammation and adipose dysfunction.

Fig. 4. Subcutaneous and visceral adipogenic progenitors (APs) differentially respond to obesity and exert opposite effects on adipose tissue inflammation. Visceral APs are composed of mesothelial and mesodermal cells, but a certain portion of these cells lose adipogenic potential and are transformed into pro-inflammatory fibrocytes in obesity. The fibrotic-APs in visceral adipose tissue (VAT) exacerbate adipose tissue inflammation via inducing fibrosis and secreting pro-inflammatory cytokines. On the other hand, subcutaneous APs suppress pro-inflammatory macrophage infiltration into subcutaneous adipose tissue (SAT) in response to gamma-aminobutyric acid (GABA). Consequently, these anti-inflammatory effects on SAT would contribute to improvement of energy metabolism in obesity.