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.

Ribas-Latre A, Hoffmann A, Gebhardt C, Weiner J, Arndt L, Raulien N, Gericke M, Gosh A, Krause K, Klöting N, Pfluger PT, Sheikh BN, Ebert T, Tönjes A, Stumvoll M, Wolfrum C, Blüher M, Wagner U, Vendrell J, Fernández-Veledo S, Heiker JT

The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.

Tindall CA, Möhlis K, Rapöhn I, Dommel S, Riedl V, Schneekönig M, Höfling C, Roßner S, Stichel J, Beck-Sickinger AG, Weiner J, Heiker JT

LRP1 is the cell-surface endocytosis receptor for vaspin in adipocytes

Rapöhn I, Elias I, Weiner J, Pujol A, Kehr S, Chadt A, Al-Hasani H, Burkhard R, Klöting N, Stumvoll M, Bosch F, Kovacs P, Heiker JT, Breitfeld J

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse.

Breitfeld J, Horn K, Le Duc GD, Velluva A, Marzi C, Grallert H, Friedrich N, Pietzner M, Völker U, Völzke H, Ahlqvist E, Mansour Aly D, Groop L, Tuomi T, Barber R, Kratzsch J, Thiery J, Isermann B, Loeffler M, Klöting N, Blüher M, Stumvoll M, Heiker JT, Tönjes A, Scholz M, Kovacs P

Genetic dissection of serum vaspin highlights its causal role in lipid metabolism

Tindall CA, Erkner E, Stichel J, Beck-Sickinger AG, Hoffmann A, Weiner J, Heiker JT

Cleavage of the Vaspin N-terminus Releases Cell-Penetrating Peptides that Affect Early Stages of Adipogenesis and Inhibit Lipolysis in Mature Adipocytes

Kunath A, Weiner J, Krause K, Rehders M, Pejkovska A, Gericke M, Biniossek ML, Dommel S, Kern M, Ribas Latre A, Schilling O, Brix K, Stumvoll M, Klöting N, Heiker JT, Blüher M

Role of Kallikrein 7 in Body Weight and Fat Mass Regulation

Tindall CA, Dommel S, Riedl V, Ulbricht D, Hanke S, Sträter N, Heiker JT

Membrane Phospholipids and Polyphosphates as Cofactors and Binding Molecules of SERPINA12 (Vaspin)

Hanke S, Tindall CA, Pippel J, Ulbricht D, Pirotte B, Reboud-Ravaux M, Heiker JT, Sträter N

Structural studies on the inhibitory binding mode of aromatic coumarinic esters to human kallikrein 7

Weiner J, Zieger K, Pippel J, Heiker JT

Molecular Mechanisms of Vaspin Action – From Adipose Tissue to Skin and Bone, from Blood Vessels to the Brain

Ulbricht D, Tindall CA, Oertwig K, Hanke S, Sträter N, Heiker JT

Zieger K, Weiner J, Kunath A, Gericke M, Krause K, Kern M, Stumvoll M, Klöting N, Blüher M, Heiker JT

Ablation of Kallikrein 7 (KLK7) in Adipose Tissue Ameliorates Metabolic Consequences of High Fat Diet-Induced Obesity by Counteracting Adipose Tissue Inflammation in vivo

Zieger K, Weiner J, Krause K, Schwarz M, Kohn M, Stumvoll M, Blüher M, Heiker JT

Vaspin Suppresses Cytokine-Induced Inflammation in 3T3-L1 Adipocytes via Inhibition of NFkappaB Pathway

Oertwig K, Ulbricht D, Hanke S, Pippel J, Bellmann-Sickert K, Sträter N, Heiker JT

Glycosylation of Human Vaspin (SERPINA12) and its Impact on Serpin Activity, Heparin Binding and Thermal Stability

Ulbricht D, Oertwig K, Arnsburg K, Saalbach A, Pippel J, Sträter N, Heiker JT

Basic Residues of beta-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

Pippel J, Küttner EB, Ulbricht D, Daberger J, Schultz S, Heiker JT, Sträter N

Crystal Structure of Cleaved Vaspin (SerpinA12)

Ulbricht D, Pippel J, Schultz S, Meier R, Sträter N, Heiker JT

A Unique Serpin P1' Glutamate and a Conserved Beta-Sheet C Arginine are Key Residues for Activity, Protease Recognition and Stability of SerpinA12 (vaspin)

Heiker JT, Klöting N, Kovacs P, Küttner EB, Sträter N, Schultz S, Kern M, Stumvoll M, Blüher M, Beck-Sickinger AG

Vaspin Inhibits Kallikrein 7 by Serpin Mechanism

Serpins and Proteases in Obesity

Serpins and Proteases in Obesity

Proteolytic Enzymes and Their Regulators in Adipose Tissue, Obesity and Inflammation

Publications

Cooperation Partners

Leipzig University, Leipzig, Germany

Universitätsklinikum Leipzig, Germany

CRC1052 "Obesity Mechanism"

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