Obesity-induced remodeling of the adipose tissue elastin network is independent of the metalloelastase MMP-12

Abstract

The extracellular matrix (ECM) plays important roles in maintaining adequate adipose tissue function and in metabolic regulation. Here we have examined the organization of a relatively unexplored adipose tissue ECM component, elastin and its response to diet induced obesity in mice. Additionally, we have explored the regulation and requirement of macrophage metalloelastase, MMP-12, in adipose tissue ECM remodeling in obesity. In visceral fat depots, elastin fibers form a mesh-like net that becomes denser with diet-induced obesity. In contrast, the elastin fibers in subcutaneous adipose depots are more linear in organization, and are tightly associated with adipose tissue macrophages (ATMs). We found that Mmp12 is produced predominantly by ATMs and can be induced with both short-and long-term high fat diet challenge and rapid remodeling induced by lipolysis. This contrasts with Mmp14 and Timp1 which are further induced only after chronic obesity in non-ATM populations. We examined obese transgenic Mmp12 ¡/¡ mice and found an increase in gene expression of ECM genes with diet-induced obesity, but showed few significant differences in metabolic parameters, elastin matrix density, or in adipose tissue inflammation. Together, these studies reveal the architecture and diet-induced regulation of the elastin matrix and suggest that MMP-12 is not required for elastin matrix remodeling or for the metabolic dysfunction that occurs with obesity.

Adipose extracellular matrix remodelling in obesity and insulin resistance

“…MMP12 (macrophage elastase) is the major MMP that degrades elastin in mice [57]. In HFD (60% fat)-induced obesity, adipose macrophages, particularly CD11c − residential macrophages (M2-like) express a high level of MMP12 [58,59]. In their study, the loss of MMP12 exacerbated HFD-induced adipose hypertrophy but improved insulin sensitivity [58].…”

“…In their study, the loss of MMP12 exacerbated HFD-induced adipose hypertrophy but improved insulin sensitivity [58]. The loss of MMP12 alone, however, did not change elastin content in adipose tissues under either normal or HFD condition [59]. Another group reported that the loss of MMP12 did not exert any significant effects on HFD (42% fat)-induced obesity [60].…”

Physical training improves visceral adipose tissue health by remodelling extracellular matrix in rats with estrogen absence: a gene expression analysis

“…Therefore, the high flexibility of ECM, as well as the adequate balance between the ECM deposition and degradation, ensures that the healthy expansion of adipose tissue occurs (Trayhurn ; Martinez‐Santibanez et al . ; Choe et al . ).…”

“…MMPs cooperate in this process (Mariman & Wang 2010). Therefore, the high flexibility of ECM, as well as the adequate balance between the ECM deposition and degradation, ensures that the healthy expansion of adipose tissue occurs (Trayhurn 2013;Martinez-Santibanez et al 2015;Choe et al 2016). On the other hand, the excessive increase in adipose tissue leads to hypoxia of the tissue that induces ECM fibrosis with a consequent reduction in the tissue plasticity, which triggers the adipose tissue metabolic dysfunction (Trayhurn 2013).…”

Identification of Matrix Metalloproteinase-12 as a Candidate Molecule for Prevention and Treatment of Cardiometabolic Disease

“…(22) Elastin is one of the major substrates of active MMP12, but it was recently shown that remodeling of the elastin network during obesity is independent of MMP12. (43) Hence, the functional impact of active MMP12 in cardiometabolic disease appears to involve other substrates. MMP12 is able to cleave other molecules, including OPN (Supplementary Figure S1).…”