The role of transforming growth factor-beta/SMAD3 in the pathogenesis of metabolic syndrome.

Abstract

Transforming growth factor-beta/SMAD3 signaling has been implicated in various metabolic processes. However, the systemic effects of SMAD3 deficiency on adiposity and insulin resistance remain obscure. We found that SMAD3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity and were resistant against the development of obesity and type 2 diabetes upon a high-fat diet

challenge, suggesting that SMAD3 is a potential target for the treatment of obesity and its associated disorders. Moreover, recent studies reveal that patients carrying SMAD3 mutations developed a syndromic form of aortic aneurysms. Yet, the underlying mechanism leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. We found that SMAD3-knockout mice developed aortic aneurysms when infused with angiotensin II, ultimately died from aortic rupture. The mechanism of these severe abnormalities involves an aberrant upregulation of nitric oxide (NO) production mediated by inducible NO synthase and an activation of matrix metalloproteinase-9.