Serpins and Proteases in Obesity
Serpins and Proteases in Obesity
A major focus of our research has been on serine protease inhibitors (serpins), their protease targets, and their interplay in adipose tissue function or dysfunction in obesity.
Proteases play crucial roles in regulating the localization, activity, and interactions of their target proteins. Due to this broad functional repertoire, they are involved in many important cellular processes such as cell proliferation and differentiation, angiogenesis, and inflammation. Proper control of proteolytic activity is essential for healthy cell and tissue function while dysregulation is a contributing factor to many pathological conditions.
In obesity, an imbalance between proteolytic activity and protease inhibition is observed and related to increased inflammation, insulin resistance, and reduced energy expenditure. Adipocyte hypertrophy, together with increased adipose tissue stresses such as hypoxia and fibrosis, contribute to local inflammation and the development of insulin resistance. Extracellular as well as intracellular proteases have been found to be dysregulated in the obese adipose tissue.
Pharmacological targeting of key proteolytic enzymes may counteract adipose tissue dysfunction and prevent progress of metabolic diseases.
The serine protease inhibitor Vaspin (SERPINA12) was initially identified in visceral adipose tissue and has the potential to counteract obesity-induced adipose tissue inflammation and insulin resistance [1, 2].
We have identified the only known protease targets as members of the kallikrein family in KLK7 and KLK14 [1, 3], while establishing vaspin determinants of protease specificity and inhibition mechanism, also with the help of numerous crystal structures (in collaboration with Prof. Norbert Sträter, Center for Biotechnology and Biomedicine, University of Leipzig) [2, 4, 5].
In addition to protease targets, we have extensively studied and characterized the binding of vaspin to cofactors such as heparin, phospholipids, and polyphosphates to elucidate the structural basis of cofactor-accelerated protease inhibition [6-8]. The proteolytic release of biologically active cell-penetrating peptides derived from the vaspin N-terminus adds to vaspins functional repertoire to regulate adipocyte biology and function .
In mice, we and others have found that overexpression of vaspin in adipose tissue can limit weight gain and adipose tissue inflammation while preserving insulin sensitivity in diet-induced obese mice . Our studies have shown that the inhibitory activity of vaspin is critical for its glucose tolerance-improving effects in insulin-resistant mice. These appear to be mediated at least in part by the target protease KLK7, which is co-expressed with vaspin in mouse pancreatic β-cells and can specifically degrade insulin . At the adipocyte level, we found that vaspin can attenuate cytokine-induced inflammation . We found that KLK7 knockout had similar effects, and KLK7-KO mice, despite significant weight gain on a high-fat diet, showed a preference for subcutaneous fat deposition with a lower inflammatory profile in all fat depots, resulting in sustained insulin sensitivity [11, 12].
1) Adv Exp Med Biol, 2019. 1111:159-188
2) ell Mol Life Sci, 2013. 70(14): 2569-83
3) Biol Chem, 2018. 399(9): 1079-1084
4) Biochem J, 2015. 470(3): 357-67
5) Biol Chem, 2016. 397(2): 111-23.
6) J Biol Chem, 2017. 292(3): 994-1004
7) Biochim Biophys Acta Proteins Proteom, 2017. 1865(9): 1188-1194
8) Molecules, 2020. 25(8): 1992
9) Adipocyte (2021), 10(1):216-31
10) Mol Cell Endocrinol, 2018. 460: 181-88
11) Cell Mol Life Sci, 2018. 75(4): 727-42
12) Biomedicines, 2021. 9(2): 131