C7 - The role of vaspin in adipose tissue thermogenesis and inflammation

This project will continue to investigate the role of vaspin and its target protease kallikrein 7 (KLK7) in adipose tissue browning and energy expenditure. We will expand the research focus on the anti-inflammatory role of vaspin/KLK7 in adipose tissue and its effect on BAT activity, EE and glucose disposal. The regulation of immune-adipose tissue interactions to support or induce adipose tissue browning and thermogenesis has been reported for other adipokines such as adiponectin and meteorin-like. On the protein level, we aim to identify further targets and coactivators of vaspin. Furthermore, newly identified KLK7 substrates as potential effectors/mediators of vaspin/KLK7 function will be investigated in vitro and in vivo. In summary, the studies of the new funding period aim to clarify the role and connection of vaspin and KLK7 in BAT, energy expenditure and adipose tissue inflammation.

Figure 1. Crystal structure of the serpin vaspin (pdb 4IF8), schematic picture of the protease inhibition mechanism of serpins and pancreas immunofluorescence with glucagon (green), Klk7 (red) and cell nuclei staining (blue).

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

PROJECT TEAM

Catherine Tindall, Phd student