Role of Hyaluronan in Human Adipogenesis: Evidence from in-Vitro and in-Vivo Studies

Abstract

Hyaluronan (HA), an extra-cellular matrix glycosaminoglycan, may play a role in mesenchymal stem cell differentiation to fat but results using murine models and cell lines are conflicting. Our previous data, illustrating decreased HA production during human adipogenesis, suggested an inhibitory role. We have investigated the role of HA in adipogenesis and fat accumulation using human primary subcutaneous preadipocyte/fibroblasts (PFs, n = 12) and subjects of varying body mass index (BMI). The impact of HA on peroxisome proliferator-activated receptor gamma (PPARγ) expression was analysed following siRNA knockdown or HA synthase (HAS)1 and HAS2 overexpression. PFs were cultured in complete or adipogenic medium (ADM) with/without 4-methylumbelliferone (4-MU = HA synthesis inhibitor). Adipogenesis was evaluated using oil red O (ORO), counting adipogenic foci, and measurement of a terminal differentiation marker. Modulating HA production by HAS2 knockdown or overexpression increased (16%, p < 0.04) or decreased (30%, p = 0.01) PPARγ transcripts respectively. The inhibition of HA by 4-MU significantly enhanced ADM-induced adipogenesis with 1.52 ± 0.18- (ORO), 4.09 ± 0.63- (foci) and 2.6 ± 0.21-(marker)-fold increases compared with the controls, also increased PPARγ protein expression (40%, (p < 0.04)). In human subjects, circulating HA correlated negatively with BMI and triglycerides (r = −0.396 (p = 0.002), r = −0.269 (p = 0.038), respectively), confirming an inhibitory role of HA in human adipogenesis. Thus, enhancing HA action may provide a therapeutic target in obesity.

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases

“…HA is increased in obese mice comparing with their counterparts and the HA inhibitor treatment improved adipose inflammation and IR [104,105]. In humans, although some studies reinforced this theory [30,106,107], a recent study has signaled that HA decreases adipogenesis [108]. Thus, further studies are needed to elucidate the role of HA in IR.…”

Collagens Regulating Adipose Tissue Formation and Functions

“…HA affects, for example, monocyte recruitment into AT, as well as the process of adipogenesis [90,91]. It has been reported to inhibit the differentiation of preadipocytes in vitro, either by knocking down or overexpressing HA synthases in the culture system [92][93][94]. In in vivo mouse models, HA accumulated in AT with HFD, and exogenous HA-degrading hyaluronidase or HA synthesis inhibitor reduced VAT accumulation and hepatosteatosis and increased insulin sensitivity [91,94].…”

Adipose Extracellular Matrix Remodeling in Obesity and Insulin Resistance

“…HA stimulates monocyte adhesion and chemotaxis through the binding to the CD44 [24], and HA is higher in obese mice comparing with their counterparts, and the inhibition of HA improve adipose tissue inflammation and insulin resistance [28]. In humans, HA decreases adipogenesis, but the role in the insulin resistance state is not completely elucidated [75]. Regarding the THBS1 is highly increased in insulin-resistant obese mice and humans [44].…”