C5 - Early Adipose Tissue Dysfunction in the Development of Obesity and Comorbidities in Children

Obesity develops in the first years of life and leads to metabolic and cardiovascular impairment already during childhood. Alterations in adipose tissue composition and function, particularly adipocyte hypertrophy, as well as adipokines, are closely related to these clinical phenomena. Such an adipose tissue dysfunction may at least in part directly contribute to the development of obesity related comorbidities. Children present earlier stages of disease and have a “shorter exposure time” to environmental factors. Studying the underlying mechanisms is less biased by pre-existing comorbidities and their treatment in children.

We hypothesize that alterations in adipose tissue biology (particularly adipocyte hypertrophy) and function (including secretory function), collectively referred to as adipose tissue dysfunction, contribute to the early development and progression of obesity and metabolic impairment in children.

We will first address which particular alterations in adipose tissue biology are related to the development of obesity and first clinical sequelae in our ongoing childhood cohorts. We will characterize factors and mechanisms that drive early adipose tissue accumulation and adipose tissue dysfunction in children. Based on merged hit lists derived from already existing expression profiles on human adipocyte biology and GWAS data from children, we will identify candidates for adipocyte hypertrophy. These will be further evaluated clinically for their relevance for fat accumulation and insulin resistance and functionally for adipogenesis. Furthermore, we will investigate the mechanisms by which the candidate mediates its effect on adipocyte biology, e.g. adipokine secretion, inflammatory processes or cellular energy metabolism and characterize how candidate gene expression in adipose tissue is linked to obesity-related metabolic and cardiovascular sequelae in children.

 

Figure 1. Adipose tissue biopsies obtained from lean and obese children are characterized for alterations in adipose tissue biology and function and their relation to the development of obesity and first clinical sequelae in children. (upper panel). To identify adipose tissue-specific regulators involved in excess fat accumulation in obesity and adipocyte hypertrophy (right panel), we will interrogate data sets for adipose tissue dysfunction/hypertrophy (a), white adipogenesis (b) and genetic risk profiles for obesity and metabolic dysfunction (c). Finally, candidate genes and respective mechanisms will be characterized for their relevance for adipose tissue biology and function in vitro an in vivo.

Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, Wood AR, Mahajan A, Tyrrell J, Robertson
NR, Rayner NW, Qiao Z, Moen GH, Vaudel M, Marsit CJ, Chen J, Nodzenski M, Schnurr TM, Zafarmand MH, Bradfield JP, Grarup N, Kooijman MN, Li-Gao R, Geller F, Ahluwalia TS, Paternoster L, Rueedi R, Huikari V, Hottenga JJ, Lyytikäinen LP, Cavadino A, Metrustry S, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Vilor-Tejedor N, Joshi PK, Painter JN, Ntalla I, Myhre R, Pitkänen N, van Leeuwen EM, Joro R, Lagou V, Richmond RC, Espinosa A, Barton SJ, Inskip HM, Holloway JW, Santa-Marina L, Estivill X, Ang W, Marsh JA, Reichetzeder C, Marullo L, Hocher B, Lunetta KL, Murabito JM, Relton CL, Kogevinas M, Chatzi L, Allard C, Bouchard L, Hivert MF, Zhang G, Muglia LJ, Heikkinen J; EGG Consortium, Morgen CS, van Kampen AHC, van Schaik BDC, Mentch FD, Langenberg C, Luan J, Scott RA, Zhao JH, Hemani G, Ring SM, Bennett AJ, Gaulton KJ, Fernandez-Tajes J, van Zuydam NR, Medina-Gomez C, de Haan HG, Rosendaal FR, Kutalik Z, Marques-Vidal P, Das S, Willemsen G, Mbarek H, Müller-Nurasyid M, Standl M, Appel EVR, Fonvig CE, Trier C, van Beijsterveldt CEM, Murcia M, Bustamante M, Bonas-Guarch S, Hougaard DM, Mercader JM, Linneberg A, Schraut KE, Lind PA, Medland SE, Shields BM, Knight BA, Chai JF, Panoutsopoulou K, Bartels M, Sánchez F, Stokholm J, Torrents D, Vinding RK, Willems SM, Atalay M, Chawes BL, Kovacs P, Prokopenko I, Tuke MA, Yaghootkar H, Ruth KS, Jones SE, Loh PR, Murray A, Weedon MN, Tönjes A, Stumvoll M, Michaelsen KF, Eloranta AM, Lakka TA, van Duijn CM, Kiess W, Körner A, Niinikoski H, Pahkala K, Raitakari OT, Jacobsson B, Zeggini E, Dedoussis GV, Teo YY, Saw SM, Montgomery GW, Campbell H, Wilson JF, Vrijkotte TGM, Vrijheid M, de Geus EJCN, Hayes MG, Kadarmideen HN, Holm JC, Beilin LJ, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widén EE, Hattersley AT, Spector TD, Kähönen M, Viikari JS, Lehtimäki T, Boomsma DI, Sebert S, Vollenweider P, Sørensen TIA, Bisgaard H, Bønnelykke K, Murray JC, Melbye M, Nohr EA, Mook-Kanamori DO, Rivadeneira F, Hofman A, Felix JF, Jaddoe VWV, Hansen T, Pisinger C, Vaag AA, Pedersen O, Uitterlinden AG, Järvelin MR, Power C, Hyppönen E, Scholtens DM, Lowe WL Jr, Davey Smith G, Timpson NJ, Morris AP, Wareham NJ, Hakonarson H, Grant SFA, Frayling TM, Lawlor DA, Njølstad PR, Johansson S, Ong KK, McCarthy MI, Perry JRB, Evans DM, Freathy RM. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet. 2019 May;51(5):804-814.


Geserick M, Vogel M, Gausche R, Lipek T, Spielau U, Keller E, Pfäffle R, Kiess WKörner A. Acceleration of BMI in Early Childhood and Risk of Sustained Obesity. N Engl J Med. 2018 Oct 4;379(14):1303-1312.


Erbs S, Broniecki H, Scheuermann K, Winzer E, Adam J, Spielau U, Woitek F, Sandri M, Zimmer M, Besler C, Kiess W, Linke A, Körner A, Mangner N. Impact of Weight Reduction During Adolescence on Parameters of Cardiac Geometry and Function in Obese Children. JACC Cardiovasc Imaging. 2018 Jul 13.


Kalenda A, Landgraf K, Löffler D, Kovacs P, Kiess W, Körner A. The BDNF Val66Met polymorphism is associated with lower BMI, lower postprandial glucose levels and elevated carbohydrate intake in children and adolescents. Pediatr Obes. 2017; Epub ahead of print.


Gesing J, Scheuermann K, Wagner IV, Löffler D, Friebe D, Kiess W, Schuster V, Körner A. NAMPT serum levels are selectively elevated in acute infectious disease and in acute relapse of chronic inflammatory diseases in children. PLoS One. 2017;12:e0183027.


Windholz J, Kovacs P, Schlicke M, Franke C, Mahajan A, Morris AP, Lemke JR, Klammt J, Kiess W, Schöneberg T, Pfäffle R, Körner A. Copy number variations in "classical" obesity candidate genes are not frequently associated with severe early-onset obesity in children. J Pediatr Endocrinol Metab. 2017;30:507-15.


Raulien N, Friedrich K, Strobel S, Rubner S, Baumann S, von Bergen M, Körner A, Krueger M, Rossol M, Wagner U. Fatty acid oxidation compensates for lipopolysaccharide-induced Warburg effect in glucose-deprived monocytes. Front Immunol. 2017;8:609.


Landgraf K, Schuster S, Meusel A, Garten A, Riemer T, Schleinitz D, Kiess W, Körner A. Short-term overfeeding of zebrafish with normal or high-fat diet as a model for the development of metabolically healthy versus unhealthy obesity. BMC Physiol. 2017;17:4.


Löffler D, Behrendt S, Creemers JW, Klammt J, Aust G, Stanik J, Kiess W, Kovacs P, Körner A. Functional and clinical relevance of novel and known PCSK1 variants for childhood obesity and glucose metabolism. Mol Metab. 2016;6:295-305.


Ehehalt S, Wiegand S, Körner A, Schweizer R, Liesenkötter KP, Partsch CJ, Blumenstock G, Spielau U, Denzer C, Ranke MB, Neu A, Binder G, Wabitsch M, Kiess W, Reinehr T. Low association between fasting and OGTT stimulated glucose levels with HbA1c in overweight children and adolescents. Pediatr Diabetes. 2016; Epub ahead of print.


Ehehalt S, Wiegand S, Körner A, Schweizer R, Liesenkötter KP, Partsch CJ, Blumenstock G, Spielau U, Denzer C, Ranke MB, Neu A, Binder G, Wabitsch M, Kiess W, Reinehr T. Diabetes screening in overweight and obese children and adolescents: choosing the right test. Eur J Pediatr. 2016; Epub ahead of print.


Rockstroh D, Löffler D, Kiess W, Landgraf K, Körner A. Regulation of human adipogenesis by miR125b-5p. Adipocyte. 2016;5:283-97.


Schreier M, Schwartze JT, Landgraf K, Scheuermann K, Erbs S, Herberth G, Pospisilik JA, Kratzsch J, Kiess W, Körner A. Osteopontin is BMI-independently related to early endothelial dysfunction in children. J Clin Endocrinol Metab. 2016;101:4161-9.


Landgraf K, Scholz M, Kovacs P, Kiess W, Körner A. FTO obesity risk variants are linked to adipocyte IRX3 expression and BMI of children - relevance of FTO variants to defend body weight in lean children? PLoS One. 2016;11:e0161739.


Dalgaard K, Landgraf K, Heyne S, Lempradi A, Longinotto J, Gossens K, Ruf M, Orthofer M, Strogantsev R, Selvaraj M, Tsai-Hsiu Lu T, Casas E, Teperino R, Surani MA, Zvetkova I, Rimmington D, Loraine Tung YCL, Lam B, Larder R, Yeo GSH, O'Rahilly S, Vavouri T, Whitelaw E, Penninger JM, Jenuwein T, Cheung CL, Ferguson-Smith AC, Coll AP, Körner A, Pospisilik JA. Trim28 haploinsufficiency triggers bi-stable epigenetic obesity. Cell. 2016;164:1-12.


Felix JF, Bradfield JP, Monnereau C, van der Valk RJ, [47 authors], Kiess W, [14 authors], Pfäffle R, [33 authors], Körner A, [9 authors], Grant SF, Jaddoe VW, Early Growth Genetics C, Bone Mineral Density in Childhood Study BC. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Hum Mol Genet. 2016;25:389-403.


Löffler D, Landgraf K, Körner A, Kratzsch J, Kirkby KC, Himmerich H. Modulation of triglyceride accumulation in adipocytes by psychopharmacological agents in vitro. J Psychiatr Res. 2015;72:37-42.


Breitling C, Gross A, Büttner P, Weise S, Schleinitz D, Kiess W, Scholz M, Kovacs P, Körner A. Genetic contribution of variants near SORT1 and APOE on LDL cholesterol independent of obesity in children. PLoS One. 2015;10:e0138064.


Schunter JA, Löffler D, Wiesner T, Kovacs P, Badenhoop K, Aust G, Tönjes A, Müller P, Baber R, Simon JC, Führer D, Pfäffle RW, Thiery J, Stumvoll M, Kiess W, Kratzsch J, Körner A. A novel FoxD3 variant is associated with vitiligo and elevated thyroid auto-antibodies. J Clin Endocrinol Metab. 2015;100:E1335-42.


Löffler D, Müller U, Scheuermann K, Friebe D, Gesing J, Bielitz J, Erbs S, Landgraf K, Wagner IV, Kiess W, Körner A. Serum irisin levels are regulated by acute strenous exercise. J Clin Endocrinol Metab. 2015;100:1289-99.


Rockstroh D, Landgraf K, Wagner IV, Gesing J, Tauscher R, Lakowa N, Kiess W, Bühligen U, Wojan M, Till H, Blüher MKörner A. Direct evidence of brown adipocytes in different fat depots in children. PLoS One. 2015;10:e0117841.


Qi Q, Downer MK, Kilpelainen TO, Taal HR, Barton SJ, Ntalla I, Standl M, Boraska V, Huikari V, Kiefte-de Jong JC, Körner A, Lakka TA, Liu G, Magnusson J, Okuda M, Raitakari O, Richmond R, Scott RA, Bailey ME, Scheuermann K, Holloway JW, Inskip H, Isasi CR, Mossaar-Rahmani Y, Jaddoe VW, Laitinen J, Lindi V, Melen E, Pitsiladis Y, Pitkanen N, Snieder H, Heinrich J, Timpson NJ, Wang T, Yuji H, Zeggini E, Dedoussis GV, Kaplan RC, Wylie-Rosett J, Loos RJ, Hu FB, Qi L. Dietary intake, FTO genetic variants and adiposity: a combined analysis of over 16,000 children and adolescents. Diabetes. 2015;64:2467-76.


van der Valk RJ, Kreiner-Moller E, Kooijman MN, Guxens M, Stergiakouli E, Saaf A, Bradfield JP, Geller F, Hayes MG, Cousminer DL, Körner A, Thiering E, Curtin JA, [42 authors], Kiess W, Mahajan A, [45 authors], Sergeyev E, [14 authors], Bonnelykke K, Jaddoe VW. A novel common variant in DCST2 is associated with length in early life and height in adulthood. Hum Mol Genet. 2015;24:1155-68.


Landgraf K, Rockstroh D, Wagner IV, Weise S, Tauscher R, Schwarze JT, Löffler D, Bühligen U, Wojan M, Till H, Kratzsch J, Kiess W, Blüher M, Körner A. Evidence of early alterations in adipose tissue biology and function and its association with obesity-related inflammation and insulin resistance in children. Diabetes. 2015;64:1249-61


Mangner N, Scheuermann K, Winzer E, Wagner I, Hoellriegel R, Sandri M, Zimmer M, Mende M, Linke A, Kiess W, Schuler G, Körner A, Erbs S. Childhood obesity: Impact on cardiac geometry and function. JACC Cardiovasc Imaging. 2014;7:1198-205.


Cousminer DL, Stergiakouli E, Berry DJ, Ang W, Groen-Blokhuis MM, Körner A, Siitonen N, Ntalla I, Marinelli M, Perry JR, Kettunen J, Jansen R, Surakka I, Timpson NJ, Ring S, Mcmahon G, Power C, Wang C, Kähönen M, Viikari J, Lehtimäki T, Middeldorp CM, Hulshoff Pol HE, Neef M, Weise S, Pahkala K, Niinikoski H, Zeggini E, Panoutsopoulou K, Bustamante M, Penninx BW; ReproGen Consortium, Murabito J, Torrent M, Dedoussis GV, Kiess W, Boomsma DI, Pennell CE, Raitakari OT, Hyppönen E, Davey Smith G, Ripatti S, McCarthy MI, Widén E; Early Growth Genetics Consortium. Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. Hum Mol Genet. 2014;23:4452-64.


Bernhard F, Landgraf K, Klöting N, Berthold A, Büttner P, Friebe D, Kiess W, Blüher M, Körner A. Functional relevance of obesity susceptibility genes from GWAs for human adipocyte differentiation. Diabetologia. 2013;56:311-22.


Körner A, Wiegand S, Hungele A, Tuschy S, Otto KP, L'allemand-Jander D, Widhalm K, Kiess W, Holl RW. Longitudinal multicenter analysis on the course of glucose metabolism in obese children. Int J Obes (Lond).  2013;37:931-6.


Landgraf K, Friebe D, Ullrich T, Kratzsch J, Dittrich K, Herberth G, Adams V, Kiess W, Erbs S, Körner A. Chemerin as a Mediator between Obesity and Vascular Inflammation in Children. J Clin Endocrinol Metab. 2012;97:E556-64.


Friebe D, Neef M, Kratzsch J, Erbs S, Dittrich K, Garten A, Petzold-Quinque S, Blüher S, Reinehr T, Stumvoll M, Blüher M, Kiess W, Körner A. Leukocytes are a major source of circulating NAMPT/PBEF/visfatin linking obesity and inflammation in humans. Diabetologia. 2011;54:1200-11.


Körner A, Neef M, Friebe D, Erbs S, Kratzsch J, Dittrich K, Blüher S, Kapellen TM, Kovacs P, Stumvoll M, Blüher M, Kiess W. Vaspin is related to gender, puberty and deteriorating insulin sensitivity in children. Int J Obes (Lond). 2011;35:578-86.


Friebe D*, Löffler D*, Schönberg M, Bernhard F, Büttner P, Landgraf K, Kiess W, Körner A. Impact of metabolic regulators on the expression of obesity associated genes FTO and NAMPT in human preadipocytes and adipocytes. PLoS One. 2011;6:e19526.


Friebe D, Neef M, Erbs S, Dittrich K, Kratzsch J, Kovacs P, Blüher M, Kiess W, Körner A. Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children. Int J Pediatr Obes. 2011;6:e345-52.


Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, for the EMPHASIS-HF Study Group [incl. Erbs S]. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11-21.


Walther C, Gaede L, Adams V, Gelbrich G, Leichtle A, Erbs S, Sonnabend M, Fikenzer K, Körner A, Kiess W, Bruegel M, Thiery J, Schuler G. Effect of increased exercise in school children on physical fitness and endothelial progenitor cells: a prospective randomized trial. Circulation. 2009;120:2251-9.


Benzinou M, Creemers JW, Choquet H, Lobbens S, Dina C, Durand E, Guerardel A, Boutin P, Jouret B, Heude B, Balkau B, Tichet J, Marre M, Potoczna N, Horber F, Le Stunff C, Czernichow S, Sandbaek A, Lauritzen T, Borch-Johnsen K, Kiess W, Körner A, Kovacs P, Jacobson P, Carlsson LMS, Walley A, Hansen T, Pedersen O, Meyre D, Froguel P. Common non-synonymous variants in PCSK1 confer risk of obesity in Europeans. Nat Genet. 2008;40:943-5.


Revollo JR*/Körner A*, Mills CA, Satoh A, Wang T, Garten A, Dasgupta B, Townsend RR, Wolberger C, Milbrandt J, Kiess W, Imai S. Nampt/PBEF/visfatin regulates insulin secretion in β-cells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007;6:363-75.


Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LMS, Kiess W, Vatin V, Lecoeur C, Delplanque J, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Kovacs P, Bougneres P, Marre M, Balkau B, Chevre JC, Froguel P. Variation in the fatso (FTO) gene contributes to both childhood obesity and severe adult obesity in the European population. Nat Genet. 2007;39:724-6.


Körner A*/Garten A*, Blüher M, Tauscher R, Kratzsch J, Kiess W. Molecular characteristics of serum visfatin and differential detection by immunoassays. J Clin Endocrinol Metab. 2007;92:4783-91.


Körner A, Kratzsch J, Gausche R, Erbs S, Kiess W. New Predictors of the Metabolic Syndrome in Children – Role of Adipocytokines? Pediatr Res. 2007;61:640-5.


Erbs S, Linke A, Schachinger V, Assmus B, Thiele H, Diederich KW, Hoffmann C, Dimmeler S, Tonn T, Hambrecht R, Zeiher AM, Schuler G. Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation. 2007;116:366-74.


Walther C, Adams V, Bothur I, Drechsler K, Fikenzer S, Sonnabend M, Bublitz B, Körner A, Erbs S, Busse M, Schuler G. Increasing physical education in high school students: effects on concentration of circulating endothelial progenitor cells. Eur J Cardiovasc Prev Rehabil. 2008;15:416-22.


Schächinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355:1210-21.


*geteilte Erstautorschaft.

PROJECT TEAM

Dr. Kathrin Landgraf, Postdoc

Elena Kempf, PhD student

Martha Hanschkow, PhD student