B6 - The Functional Relevance of Adhesion GPCR in Adipose Tissue

Genome-wide association studies and transcriptomic data related several adhesion G protein-coupled receptors (aGPCRs) to metabolic characteristics such as obesity (GPR133/ADGRD1) or LDL cholesterol levels (CELSR2/ADGRC2). This family of receptors is defined by their large size and modular composition. Only recent discoveries have provided an understanding of the mechanisms that govern the activation of these GPCRs. It is thought that aGPCR incitement requires the interplay between endogenous ligands, the tethered agonist sequence and mechanical force. This rather unusual mode of action might unravel unknown principles of metabolic regulation and adipocyte function and may lead to the discovery of new treatment paradigms.

Little is known about the role of aGPCRs in adipose tissue. In example, one representative, GPR116/ADGRF5, has been shown to be critical for adipocyte differentiation in vitro. The same study reported glucose intolerance and insulin resistance in mice when specifically knocked out in adipose tissue. The scarce published data available claims only one other aGPCR, namely CD97/ADGRE5, to be expressed in adipocytes. Yet, our own preliminary data suggest a regulated expression of at least two other aGPCRs, GPR133 and Celsr2, during adipocyte differentiation. In this project, we clarify the functional relevance of aGPCRs in adipose tissue. Thus, the expression profiles of all aGPCRs in white and brown adipose tissue at several differentiation states will be determined. Further, we will determine the effect of aGPCR activation on adipocyte function regarding lipolysis, glucose uptake, cell respiration, and hormone expression and secretion in adipocytes.

Figure 1: Adhesion G protein-coupled receptors (aGPCRs) modulate adipocyte function. Several members of the aGPCR family have been identified to be differentially regulated in adipocytes and adipose tissue. We propose that aGPCRs can modify adipocyte function and fatty acid composition through G protein-mediated functions in vitro and in vivo.

PKA: protein kinase A, HSL: hormone-sensitive lipase, ATGL: adipose triglyceride lipase, TG: triglyceride, FFA: free fatty acid, p116: agonistic peptide of GPR116 (an aGPCR that is endogenously expressed in adipose tissue), w/o: without.

Röthe J, Thor D, Winkler J, Knierim AB, Binder C, Huth S, Kraft R, Rothemund S, Schöneberg T, Prömel S. Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release. Cell Rep. 2019 Feb 5;26(6):1573-1584.


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Schöneberg T, Meister J, Knierim AB, Schulz A. The G protein-coupled receptor GPR34 - The past 20 years of a grownup. Pharmacol Ther. 2018 Apr 22. pii: S0163-7258(18)30071-8.


Lede V, Meusel A, Garten A, Popkova Y, Penke M, Franke C, Ricken A, Schulz A, Kiess W, Huster DSchöneberg TSchiller J. Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor. PLoS One. 2017;12:e0172000.


Popkova Y, Schiller J. TAG suppression by CsCl addition. Rapid Commun Mass Spetrom. 2017;31:411-8.


Engel KM, Schiller J. A comparison of PC oxidation products as detected by MALDI-TOF and ESI-IT mass spectrometry. Chem Phys Lipids. 2017;203:33-45.


Schröter J, Schiller J. Chlorinated phospholipids and fatty acids: (patho)physiological relevance, potential toxicity, and analysis of lipid chlorohydrins. Oxid Med Cell Longev. 2016;2016:8386362.


Lede V, Franke C, Meusel A, Teupser D, Ricken A, Thiery J, Schiller JHuster DSchöneberg T, Schulz A. Severe atherosclerosis and hypercholesterolemia in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor. PLoS One. 2016;11:e0167888.


Stelzner K, Herbert D, Popkova Y, Lorz A, Schiller J, Gericke M, Klöting N, Blüher M, Franz S, Simon JC, Saalbach A. Free fatty acids sensitize dendritic cells to amplify TH1/TH17-immune responses. Eur J Immunol. 2016;46:2043-53.


Schröter J, Griesinger H, Reuß E, Schulz M, Riemer T, Süß R, Schiller J, Fuchs B. Unexpected products of the hypochlorous acid-induced oxidation of oleic acid: A study using high performance thin-layer chromatography-electrospray ionization mass spectrometry. J Chromatogr A. 2016;1439:89-96.


Popkova Y, Meusel A, Breitfeld J, Schleinitz D, Hirrlinger J, Dannenberger D, Kovacs P, Schiller J. Nutrition-dependent changes of mouse adipose tissue compositions monitored by NMR, MS, and chromatographic methods. Anal Bioanal Chem. 2015;407:5113-23.


Griesinger H, Fuchs B, Süß R, Matheis K, Schulz M, Schiller J. The thicknesses of the stationary phase determines the quality of TLC/MALDI mass spectra of lipids. Anal Biochem. 2014;451:45-7.


Jaskolla TW, Onischke K, Schiller J. 2,5-dihydroxybenzoic acid salts for matrix-assisted laser desorption/ionizatioin time-of-flight mass spectrometric lipid analysis: Simplified spectra interpretation and insights into gasphase fragmentation. Rapid Commun Mass Spetrom. 2014;28:1353-63.


Zschörnig K, Schiller J. A simple method to generate oxidized phosphatidylcholines im amounts close to one milligram. Chem Phys Lipids. 2014;184:30-7.


Eibisch M, Popkova Y, Süß R, Schiller J, Dannenberger D. Evaluation of a commercial enzymatic test kit regarding the quantitative analysis of different free fatty acids. Anal Bioanal Chem. 2014;406:7410-5.


Pirkl A, Meier M, Popkova Y, Letzel M, Schnapp A, Schiller J, Dreisewerd K. Analysis of free fatty acids by ultraviolet laser desorption ionization mass spectrometry using insect wings as hydrophobic sample substrates. Anal Chem. 2014;86:10763-71.


Scheidt HA, Meyer T, Nikolaus J, Baek DJ, Haralampiev I, Thomas L, Bittmann R, Müller P, Herrmann A, Huster D. Cholesterol[1]s Aliphatic Side Chain Modulates Membrane Properties. Angew Chem Int Ed. 2013;52:12848–51.


Weber F, Böhme J, Scheidt HA, Gründer W, Rammelt S, Hacker M, Schulz-Siegmund M, Huster D31P and 13C solid-state NMR spectroscopy to study collagen synthesis and biomineralization in polymer-based bone implants. NMR Biomed. 2012;25:464-75.


Fuchs B, Süß R, Teuber K, Eibisch M, Schiller J. Application of TLC to the analysis of lipids. J Chromatogr A. 2011;1218:2754-74.


Sträter N, Marek S, Kuettner EB, Kloos M, Keim A, Brüser A, Kirchberger J, Schöneberg T. Molecular architecture and structural basis of allosteric regulation of eukaryotic phosphofructokinases. FASEB J. 2011;25:89-98.


Bohnekamp J, Schöneberg T. Cell adhesion receptor GPR133 couples to Gs protein. J Biol Chem. 2011; 286: 41912-6.


Engel KMY, Schröck K, Teupser D, Holdt LM, Tönjes A, Kern M, Dietrich K, Kovacs P, Krügel U, Scheidt HA, Schiller JHuster D, Brockmann GA, Augustin M, Thiery J, Blüher M, Stumvoll M, Schöneberg T, Schulz A. Reduced food intake and body weight in mice deficient for the G protein-coupled receptor GPR82. PLoS One. 2011;6:e29400.


Fuchs B, Süß R, Schiller J. An update of MALDI-TOF mass spectrometry in lipid research. Progr Lipid Res. 2010;49:450-75.


Jaskolla T, Fuchs B, Karas M, Schiller J. The new matrix 4-chloro-α-cyanocinnamic acid allows the detection of phosphatidylethanolamine chloramines by MALDI-TOF mass spectrometry. J Am Soc Mass Spectrom. 2009;20:867-74.


Richter G, Schober C, Süß R, Fuchs B, Birkemeyer C, Schiller J. Comparison of the positive and negative ion electrospray ionization and matrix-assisted laser desorption and ionization time-of-flight mass spectra of the reaction products of phosphatidylethanolamines and hypochlorous acid. Anal Biochem. 2008;376:157-9.


Bunge A, Müller P, Stöckl M, Herrmann A, Huster D. Characterization of the ternary mixture of sphingomyelin, POPC, and cholesterol. Support for an inhomogeneous lipid distribution at high temperature. Biophys J. 2008;94:2680-90.


Stäubert C, Tarnow P, Brumm H, Pitra C, Gudermann T, Grüters A, Schöneberg T, Biebermann H, Römpler H. Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor. Endocrinology. 2007;148:4642-8.


Huster D, Scheidt HA, Arnold K, Herrmann A, Müller P. Desmosterol may replace cholesterol in biological membranes. Biophys J. 2005;88:1838-44.


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PROJECT TEAM

Dr. Doreen Thor, Postdoc

Elisabeth Jäger, Phd student

Anna Peters, Phd student

Franziska Münzer, Phd student

Anja Wieprecht, Phd student

Annelie Schulze, Phd student

Tomáš Suchý, Phd student

Christian Ullmann, Phd student

Viktoria Groß, Phd student