Serpins and Proteases in Obesity

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

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.

2023 FEBS J, doi: 10.1111/febs.16991

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

2023 Front Endocrinol, 14:1146454.

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.

2023 Obesity, 31, 2862-2874.

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

2021 Adipocyte, 10(1):216-31

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

2021 Biomedicines, 9(2): 131

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

2020 Molecules, 25(8): 1992

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)

2020 J Med Chem, 63: 5723-5733.

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

2019 Protein Reviews. Advances in Experimental Medicine and Biology, 1111:159-188.

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

2018 Biol Chem, 399(9): 1079-1084

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