Adipose tissue stiffness in the development of metabolic diseases.

Obesity, defined as an expansion of white adipose tissue, is also accompanied by interstitial fibrosis and overexpression of extracellular matrix (ECM) in adipose tissue in recent studies. We hypothesize that obesity induces adipose tissue ECM crosslinking and stiffening, leading to adipocyte dysfunction. First, we applied a collagen gel system to investigate the effect of ECM stiffness on adipogenesis and mature adipocyte functions. Our results showed that increased ECM stiffness impaired adipogenesis; and blunted the sensitivity to insulin and lipolytic cues, as well as secretion of adipokines, in differentiated adipocytes. In contrast, increased ECM stiffness exacerbated the sensitivity to inflammatory stimulation. Next, we found that ob/ob adipose tissue exhibited an increased signal in the polarized view of picrosirius red stained section, as well as increased crosslinks and aggregated collagen in second harmonics generation (SHG) imaging. These results suggest that ECM crosslinking was upregulated in the adipose tissue of obese mice. Ex vivo crosslinking inhibition in ob/ob adipose tissue explants increased insulin sensitivity, adiponectin expression and lipolytic activity. Finally, in vivo crosslinking inhibition reversed metabolic impairments and adipocyte functional signature genes in ob/ob mice. Taken together, our study underscores that adipose tissue crosslinking and stiffening may orchestrate metabolic disorders resulting from adipocyte dysfunction in obesity.