C7 - Molecular mechanisms of the vaspin-KLK7 axis in obesity and diabetes

This project investigates the roles and interplay of the serpin vaspin and its target proteases in adipose tissue (AT) inflammation, insulin resistance and energy expenditure. Identifying vaspin target proteases such as KLK7, cofactors and most recently, an adipocyte cell-surface receptor, we have established vaspin and KLK7 as counteracting molecules in obesity-induced AT inflammation and vaspin as auto-regulatory protein in BAT thermogenesis.


Figure: Top left: thermal imaging of a laboratory mouse. Top right: Detail of vaspin crystal structure (pdb: 4IF8) showing the RCL cleavage site residues M378 and E379. Bottom left: Gel-based analysis of vaspin-KLK7 complex formation. Bottom right: Adipored lipid stain in fully differentiated primary adipocytes. Center: Model of vaspin (blue/red, pdb: 4IF8) in transient Michaelis complex with KLK7 (pink), with bridging heparin chain and three glycosylation PTMs.

Weiner J, Roth L, Kranz M, Brust P, Boelen A, Klöting N, Heiker JT, Blüher M, Tönjes A, Pfluger PT, Stumvoll M, Mittag J, Krause K. Leptin counteracts hypothermia in hypothyroidism through its pyrexic effects and by stabilizing serum thyroid hormone levels. Mol Metab. 2021 Oct 2:101348. 

Schaffert A, Krieg L, Weiner J, Schlichting R, Ueberham E, Karkossa I, Bauer M, Landgraf K, Junge KM, Wabitsch M, Lehmann J, Escher BI, Zenclussen AC, Körner A, Blüher M, Heiker JT, von Bergen M, Schubert K. Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ. Int. 2021 Jun 27;156:106730.

Ribas-Latre A, Santos RB, Fekry B, Tamim YM, Shivshankar S, Mohamed AMT, Baumgartner C, Kwok C, Gebhardt C, Rivera A, Gao Z, Sun K, Heiker JT, Snyder BE, Kolonin MG, Eckel-Mahan KL. Cellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue. Nat Commun . 2021 Jun 9;12(1):3482

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. Adipocyte. 2021 Dec;10(1):216-231.

Epperlein S, Gebhardt C, Rohde K, Chakaroun R, Patt M, Schamarek I, Kralisch S,[nbsp]Heiker JT, Scholz M, Stumvoll M, Kovacs P, Breitfeld J, Tönjes A. The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits. Biomedicines. 2021 Mar 29;9(4):345.

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. Biomedicines 2021, 9, 131.

Massier L, Chakaroun R, Kovacs P, Heiker JT. Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability. Gut . 2020 Oct 9;gutjnl-2020-323026.

Kunath A, Heiker JT, Kern M, Kosacka J, Flehmig G, Stumvoll M, Kovacs P, Blüher M, Klöting N. Nicotinamide Nucleotide Transhydrogenase (Nnt) Is Related to Obesity in Mice. Horm Metab Res . 2020 Jul 6.

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-Related Peptidase 7. J Med Chem. 2020 Jun 11;63(11):5723-5733.

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). Molecules. 2020 Apr 24;25(8):1992.

Suchý T, Zieschang C, Popkova Y, Kaczmarek I, Weiner J, Liebing AD, Çakir MV, Landgraf K, Gericke M, Pospisilik JA, Körner A, Heiker JT, Dannenberger D, Schiller J, Schöneberg T, Liebscher I, Thor D. The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance. Int J Obes (Lond). 2020 Mar 19.

Heinitz S, Gebhardt C, Piaggi P, Krüger J, Heyne H, Weiner J, Heiker JT, Stumvoll M, Blüher M, Baier L, Rudich A, Kovacs P, Tönjes A. Atg7-knockdown reduces chemerin secretion in murine adipocytes. J Clin Endocrinol Metab. 2019 Jun 21. pii: jc.2018-01980.

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. Adv Exp Med Biol. 2018 Jul 27.

Scheffler L, Crane A, Heyne H, Tönjes A, Schleinitz D, Ihling HC, Stumvoll M, Freire R, Fiorentino M, Fasano A, Kovacs P and Heiker JT. Widely Used commercial elisa. Does not Detect Precursor of haptoglobin2, but recognizes Properdin as a Potential second Member of the Zonulin Family. Front Endocrinol (Lausanne). 2018 Feb 5;9:22

Ulbricht D, Tindall CA, Oertwig K, Hanke S, Sträter N, Heiker JT. Kallikrein-related peptidase 14 is the second KLK protease targeted by the serpin vaspin. Biological Chemistry  2018 Feb 1.

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. Adv Exp Med Biol. 2018 Jul 27.

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. Cell Mol Life Sci. 2017; Epub ahead of print.

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 NFkB pathway. Mol Cell Endocrinol. 2017; Epub ahead of print.

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. Biochim Biophys Acta. 2017;1865:1100-3.

Buerger F, Müller S, Ney N, Weiner J, Heiker JT, Kallendrusch S, Kovacs P, Schleinitz D, Thiery J, Stadler SC, Burkhardt R. Depletion of Jmjd1c impairs adipogenesis in murine 3T3-L1 cells. Biochim Biophys Acta. 2017;1863:1709-17.

Weiner J, Rohde K, Krause K, Zieger K, Klöting N, Kralisch S, Kovacs P, Stumvoll M, Blüher M, Böttcher Y, Heiker JT. Brown adipose tissue (BAT) specific vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation. Mol Met. 2017; Epub ahead of print.

Ulbricht D, Oertwig K, Arnsburg K, Saalbach A, Pippel J, Sträter N, Heiker JT. Basic residues of ß-sheet a contribute to heparin binding and activation of vaspin (serpin A12). J Biol Chem. 2017;292:994-1004.

Hankir MK, Kranz M, Keipert S, Weiner J, Andreasen SG, Kern M, Patt M, Klöting N, Heiker JT, Hesse S, Brust P, Jastroch M, Fenske W. Dissociation between brown adipose tissue 18F-FDG uptake and thermogenesis in uncoupling protein 1 deficient mice. J Nucl Med. 2017; Epub ahead of print.

Weiner J, Kranz M, Klöting N, Kunath A, Steinhoff K, Rijntjes E, Köhrle J, Zeisig V, Hankir M, Gebhardt C, Deuther-Conrad W, Heiker JT, Fasshauer M, Stumvoll M, Blüher M, Sabri O, Hesse S, Brust P, Tönjes A, Krause K. Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissue in mice. Sci Rep. 2016;6:38124.

Hankir MK, Kranz M, Gnad T, Weiner J, Wagner S, Deuther-Conrad W, Bronisch F, Steinhoff K, Luthardt J, Klöting N, Hesse S, Seibyl JP, Sabri O, Heiker JT, Blüher M, Pfeifer A, Brust P, Fenske WK. A novel thermoregulatory role for PDE10A in mouse and human adipocytes. EMBO Mol Med. 2016;8:796-812.

Saalbach A, Tremel J, Herbert D, Schwede K, Wandel E, Schirmer C, Anderegg U, Beck-Sickinger AG, Heiker JT, Schultz S, Magin T, Simon JC. Anti-inflammatory action of keratinocyte-derived vaspin: relevance for the pathogenesis of psoriasis. Am J Pathol. 2016;186:639-51.

Pippel J, Küttner EB, Ulricht D, Daberger J, Schultz S, Heiker JT, Sträter N. Crystal structure of cleaved vaspin (serpinA12). Biol Chem. 2016;397:111-23.

Krause K, Weiner J, Hönes S, Klöting N, Rijntjes E, Heiker JT, Gebhardt C, Köhrle J, Führer D, Steinhoff K, Hesse S, Moeller LC, Tönjes A. The effects of thyroid hormones on gene expression of acyl-coenzyme A thioesterases in adipose tissue and liver of mice. Eur Thyroid J. 2015;4(suppl 1):59-66.

Mardinoglu A, Heiker JT, Gärtner D, Björnson E, Schön MR, Flehmig G, Klöting N, Krohn K, Fasshauer M, Stumvoll M, Nielsen J, Blüher M. Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue. Sci Rep. 2015;5:14841.

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). Biochem J. 2015;470:357-67.

Kern M, Kosacka J, Hesselbarth N, Brückner J, Heiker JT, Flehmig G, Klöting I, Kovacs P, Matz-Soja M, Gebhardt R, Krohn K, Sales S, Abshagen K, Shevchenko A, Stumvoll M, Blüher M, Klöting N. Liver-restricted Repin1 deficiency improves whole body insulin sensitivity, alters lipid metabolism and causes secondary changes in adipose tissue in mice. Diabetes. 2014;63:3295-309.

Heiker JT*, Kunath A*, Kosacka J, Flehmig G, Knigge A, Kern M, Stumvoll M, Kovacs P, Blüher M, Klöting N. Identification of genetic loci associated with different responses to high fat died induced obesity (DIO) in C57BL/6N and C57BL/6J substrains. Physiol Genomics. 2014;46:377-84.

Heiker JT. Vaspin (serpinA12) in obesity, insulin resistance, and inflammation. J Pept Sci. 2014;20:299-306.

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. Cell Mol Life Sci. 2013;70:2569-83.

Breitfeld J, Heiker JT, Böttcher Y, Schleinitz D, Tönjes A, Weidle K,Krause K, Küttner EB, Scholz M, Kiess W, Sträter N, Beck-Sickinger AG, Stumvoll M, Körner A, Blüher M, Kovacs P. Analysis of a Rare Functional Truncating Mutation rs61757459 in Vaspin(SERPINA12) on Circulating Vaspin Levels. J Mol Med. 2013;91:1285-92.

Schultz S, Saalbach A, Heiker JT, Zellmann T, Simon JC, Beck-Sickinger AG. Proteolytic Activation of Prochemerin by Kallikrein 7 Breaks an Ionic Linkage and Results in C-terminal Rearrangement. Biochem J. 2013;452:271-80.

Heiker JT, Klöting N. Replication Initiator 1 in Adipose Tissue Function and Human Obesity. Vitam Horm. 2013;91:97-105.

Heiker JT, Kern M, Kosacka J, Flehmig G, Stumvoll M, Shang E, Lohmann T, Dreßler M, Kovacs P, Blüher M, Klöting N. Nicotinamide Nucleotide Transhydrogenase (NNT) Expression is Related to Obesity in Humans. Obesity. 2013;21:529-34.

Kern M, Knigge A, Heiker JT, Kosacka J, Stumvoll M, Kovacs P, Blüher M, Klöting N. C57BL/6JRj Mice are Protected against Diet Induced Obesity (DIO). Biochem Biophys Res Comm. 2012;417:717-20.

Klöting N, Kovacs P, Kern M, Heiker JT, Fasshauer M, Schön MR, Stumvoll M, Beck-Sickinger AG, Blüher M. Central Vaspin Administration Acutely Reduces Food Intake and has Sustained Blood Glucose-lowering Effects. Diabetologia. 2011;54:1819-23.

*geteilte Erstautorschaft


Lisa Christen, PhD student

Inka Rapöhn, PhD student

Kevin Möhlis, PhD student