ADAM 12 Protease Induces Adipogenesis in Transgenic Mice

Abstract

ADAM 12 (meltrin-alpha) is a member of the ADAM (a disintegrin and metalloprotease) family. ADAM 12 functions as an active metalloprotease, supports cell adhesion, and has been implicated in myoblast differentiation and fusion. Human ADAM 12 exists in two forms: the prototype membrane-anchored protein, ADAM 12-L, and a shorter secreted form, ADAM 12-S. Here we report the occurrence of adipocytes in the skeletal muscle of transgenic mice in which overexpression of either form is driven by the muscle creatine kinase promoter. Cells expressing a marker of early adipogenesis were apparent in the perivascular space in muscle tissue of 1- to 2-week-old transgenic mice whereas mature lipid-laden adipocytes were seen at 3 to 4 weeks. Moreover, female transgenics expressing ADAM 12-S exhibited increases in body weight, total body fat mass, abdominal fat mass, and herniation, but were normoglycemic and did not exhibit increased serum insulin, cholesterol, or triglycerides. Male transgenics were slightly overweight and also developed herniation but did not become obese. Transgenic mice expressing a truncated form of ADAM 12-S lacking the prodomain and the metalloprotease domain did not develop this adipogenic phenotype, suggesting a requirement for ADAM 12 protease activity. This is the first in vivo demonstration that an ADAM protease is involved in adipogenesis.

Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice

“…Previously, our laboratory reported that activated PAR-1 led to cardiac remodeling (21) and that inhibition of MMPs prevented connexin-43 degradation and ameliorated heart failure (13). In the present study, we found that, other than increased expression of PAR-1, ADAM-12, an enzyme involved in cell adhesion and myoblast differentiation and fusion (15), was also overexpressed in AVF animals. This finding suggests that increased activity of PAR-1 could lead to activation of several proteolytic events.…”

Matrix Metalloproteinases Are Differentially Expressed in Adipose Tissue during Obesity and Modulate Adipocyte Differentiation

“…Alternatively, TIMP-3 suppression might influence the activity of the ADAM (a disintegrin and metalloprotease) family of metalloproteinases because reports indicated that TIMP-3 exhibits inhibitory activity against several ADAMs that are not inhibited by other TIMPs, such as tumor necrosis factor ␣ convertase (ADAM-17) (7,36). In support of this, Kawaguchi et al (40) recently found that female transgenic mice expressing ADAM-12 become obese, demonstrating that an ADAM metalloproteinase might also regulate adipogenesis.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…The complex but conserved structure of ADAM family members endows these proteins with various abilities leading to their key contribution to various physiological functions such as, for instance, fertilization [15,32], neurogenesis [33], adipogenesis [34,35] and myogenesis [36]. ADAMs and ADAMTSs are involved in a complex molecular network of reciprocal interactions.…”