B4 - Identification and functional characterisation of a novel obesity gene in a new spontaneous C57BL/6 model (Obis)

The genetic architecture of body weight and body composition is subjected to polygenetic or monogenetic inheritance. A handful of monogenic disorders leading to early, severe obesity in humans have been identified. All genes affect the central regulation of appetite. In a C57BL/6N inbred strain we identified a new spontaneous monogenetic mutation (named Obis) characterized by a fat-depot specific massive subcutaneous obesity, without effecting the central regulation of appetite. This phenotype is also present in human obesity and the affected gene/mutation is unknown. First backcrossing (BC1) studies indicate that the observed phenotype is monogenic inherited. They further indicate that its inheritance pattern is autosomal recessive. The genome analysis of known monogenic mutations (leptin, leptin receptor, MCR4 gene) causing monogenic obesity revealed no changes between lean littermates and obese Obis mice. Therefore, we believe that the mutation must be an unknown gene. We aim at identifying the causative variant and functionally characterize its downstream effects that lead to the Obis phenotype. QTL analysis of BC1 animals, expression QTL analysis, targeted sequencing of the QTL region, as well as functional analysis of the downstream affected genes will be performed to identify and extensively characterize the genetic changes behind this novel phenotype.

Figure 1. Mature cultured adipocytes isolated from SVF from subcutaneous adipose tissue of BL/6, db/db and Obis mice.


Rolle-Kampczyk U, Gebauer S, Haange SB, Schubert K, Kern M, Moulla Y, Dietrich A, Schön MR, Klöting N, von Bergen M, Blüher M. Accumulation of distinct persistent organic pollutants is associated with adipose tissue inflammation. Sci Total Environ. 2020 Dec 15;748:142458.

Klöting N, Ristow M, Blüher M. Effects of exercise on ACE2. Obesity (Silver Spring). 2020 Sep 17.

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.

Nono Nankam PA, Blüher M, Kehr S, Klöting N, Krohn K, Adams K, Stadler PF, Mendham AE, Goedecke JH. Distinct abdominal and gluteal adipose tissue transcriptome signatures are altered by exercise training in African women with obesity. Sci Rep. 2020 Jun 24;10(1):10240.

Dommel S, Berger C, Kunath A, Kern M, Gericke M, Kovacs P, Guiu-Jurado E, Klöting N, Blüher M. The Fabp4-Cre-model is insufficient to study Hoxc9 function in adipose tissue. Biomedicines . 2020 Jun 29;8(7):E184.

Jacobi T, Massier L, Klöting N, Horn K, Schuch A, Ahnert P, Engel C, Löffler M, Burkhardt R, Thiery J, Tönjes A, Stumvoll M, Blüher M, Doxiadis I, Scholz M, Kovacs P. HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non–Insulin-Treated Type 2 Diabetes. J Clin Endocrinol Metab. 2020 Mar 1;105(3).

Wittrisch S, Klöting N, Mörl K, Chakaroun R, Blüher M, Beck-Sickinger AG. NPY1R-targeted peptide-mediated delivery of a dual PPARα/γ agonist to adipocytes enhances adipogenesis and prevents diabetes Progression. Mol Metab. 2020 Jan;31:163-180.

Abshagen K, Berger C, Dietrich A, Schütz T, Wittekind C, Stumvoll M, Blüher M, Klöting N. A Human REPIN1 Gene Variant: Genetic Risk Factor for the Development of Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol. 2020 Jan;11(1):e00114.

Klöting N, Kern M, Moruzzi M, Stumvoll M, Blüher M. Tamoxifen treatment causes early hepatic insulin resistance. Acta Diabetol. 2020 Jan 6.

Zelicha H, Kaplan A, Yaskolka Meir A, Tsaban G, Rinott E, Shelef I, Tirosh A, Brikner D, Pupkin E, Qi L, Thiery J, Stumvoll M, Klöting N, von Bergen M, Ceglarek U, Blüher M, Stampfer MJ, Shai I. The Effect of Wolffia globosa Mankai, a Green Aquatic Plant, on Postprandial Glycemic Response: A Randomized Crossover Controlled Trial. Diabetes Care. 2019 Jul;42(7):1162-1169

Abshagen K, Mense L, Fischer F, Liebig M, Schaeper U, Navarro G, Glass Ä, Frank M, Klöting N, Vollmar B. Repin1 deficiency in liver tissue alleviates NAFLD progression in mice. J Adv Res. 2018 Nov 22;16:99-111.

Kosacka J, Woidt K, Toyka KV, Paeschke S, Klöting N, Bechmann I, Blüher M, Thiery J, Ossmann S, Baum P, Nowicki M. The role of dietary non-heme iron load and peripheral nerve inflammation in the development of peripheral neuropathy (PN) in obese non-diabetic leptin-deficient ob/ob mice. Neurol Res. 2019 Jan 13:1-13.

Abshagen K, Degenhardt B, Liebig M, Wendt A, Genz B, Schaeper U, Stumvoll M, Hofmann U, Frank M, Vollmar B, Klöting N. Liver-specific Repin1 deficiency impairs transient hepatic steatosis in liver regeneration. Sci Rep. 2018 Nov 15;8(1):16858.

Giusepponi ME, Kern M, Chakaroun R, Wohland T, Kovacs P, Dietrich A, Schön MR, Krohn K, Pucci M, Polidori C, Micioni Di Bonaventura MV, Stumvoll M, Blüher M, Cifani C, Klöting N. Gene expression profiling in adipose tissue of Sprague Dawley rats identifies olfactory receptor 984 as a potential obesity treatment target. Biochem Biophys Res Commun. 2018 Nov 2;505(3):801-806.

Hollenbach M, Klöting N, Sommerer I, Lorenz J, Heindl M, Kern M, Mössner J, Blüher M, Hoffmeister A. p8 deficiency leads to elevated pancreatic beta cell mass but does not contribute to insulin resistance in mice fed with high-fat diet. PLoS One. 2018 Jul 24

Wagner IV, Sahlin L, Savchuk I, Klöting N, Svechnikov K, Söder O. Adipose Tissue is a Potential Source of Hyperandrogenism in Obese Female Rats. Obesity (Silver Spring). 2018 Jul;26(7):1161-1167.

Krüger J, Berger C, Weidle K, Schleinitz D, Tönjes A, Stumvoll M, Blüher M, Kovacs P, Klöting N. Metabolic effects of genetic variation in the human REPIN1 gene. Circ Genom Precis Med. 2018 May;11(5):e001992.

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.

Hesselbarth N, Kunath A, Kern M, Gericke M, Mejhert N, Ryden M, Stumvoll M, Blüher M, Klöting N. Repin1 deficiency in adipose tissue improves whole-body insulin sensitivity, and lipid metabolism. Int J Obes (Lond). 2017; Epub ahead of print.

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.

Kralisch S, Hoffmann A, Klöting N, Bachmann A, Kratzsch J, Stolzenburg JU, Dietel A, Beige J, Anders M, Bast I, Blüher M, Zhang MZ, Harris RC, Stumvoll M, Fasshauer M, Ebert T. FSTL3 is increased in renal dysfunction. Nephrol Dial Transplant. 2017; Epub ahead of print.

Haim Y, Blüher M, Konrad D, Goldstein N, Klöting N, Harman-Boehm I, Kirshtein B, Ginsberg D, Tarnovscki T, Gepner Y, Shai I, Rudich A. ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tisue in obesity, molecularly defining a human dys-metabolic obese phenotype. Mol Metab. 2017;6:725-36.

Braune J, Weyer U, Matz-Soja M, Hobusch C, Kern M, Kunath A, Klöting N, Kralisch S, Blüher M, Gebhardt R, Zavros Y, Bechmann I, Gericke M. Hedgehog sinaling in myeloid cells impacts on body weight, adipose tissue inflammation and glucose metabolism. Diabetologia. 2017;60:889-99.

Guiu-Jurado E, Unthan M, Böhler N, Kern M, Landgraf K, Dietrich A, Schleinitz D, Ruschke K, Klöting N, Faßhauer M, Tönjes A, Stumvoll M, Körner A, Kovacs P, Blüher M. Bone morphogenetic protein 2 (BMP2) may contribute to partition of energy storage into visceral and subcutaneous fat depots. Obesity (Silver Spring). 2016; Epub ahead of print.

Weingarten A, Turchetti L, Krohn K, Klöting I, Kern M, Kovacs P, Stumvoll M, Blüher M, Klöting N. Novel genes on rat chromosome 10 are linked to body fat mass, preadipocyte number and adipocyte size. Int J Obes (Lond). 2016; Epub ahead of print.

Kunath A, Hesselbarth N, Gericke M, Kern M, Dommel S, Kovacs P, Stumvoll M, Blüher M, Klöting N. Repin1 deficiency improves insulin sensitivity and glucose metabolism in db/db mice by reducing adipose tissue mass and inflammation. Biochem Biophys Res Commun. 2016;478:398-402.

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.

Pfeiffer S, Krüger J, Maierhofer A, Böttcher Y, Klöting N, El Hajj N, Schleinitz D, Schön MR, Dietrich A, Fasshauer M, Lohmann T, Dreßler M, Stumvoll M, Haaf T, Blüher M, Kovacs P. Hypoxia-inducible factor 3A gene expression and methylation in adipose tissue is related to adipose tissue dysfunction. Sci Rep. 2016;6:27969.

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.

Hoffmann A, Manjowk GM, Wagner V, Klöting N, Ebert T, Jessnitzer B, Lössner U, Stukenborg JB, Blüher M, Stumvoll M, Söder O, Svechnikov K, Fasshauer M, Kralisch S. Leptin within the subphysiological to physiological range dose-dependently improves male reproductive function in an obesity mouse model. Endocrinology. 2016;157:2461-8.

Baum P, Kosacka J, Estrela-Lopis I, Woidt K, Serke H, Paeschke S, Stockinger M, Klöting N, Blüher M, Dorn M, Classen J, Thiery J, Bechmann I, Toyka KV, Nowicki M. The role of nerve inflammation and exogenous iron load in experimental peripheral diabetic neuropathy (PDN). Metabolism. 2016;65:391-405.

Brune JE, Kern M, Kunath A, Flehmig G, Schön MR, Lohmann T, Dressler M, Dietrich A, Fasshauer M, Kovacs P, Stumvoll M, Blüher M, Klöting N. Fat depot-specific expression of HOXC9 and HOXC10 may contribute to adverse fat distribution and related metabolic traits. Obesity (Silver Spring). 2016;24:51-9.

Klöting N, Hesselbarth N, Gericke M, Kunath A, Biemann R, Chakaroun R, Kosacka J, Kovacs P, Kern M, Stumvoll M, Fischer B, Rolle-Kampczyk U, Feltens R, Otto W, Wissenbach DK, von Bergen M, Blüher M. Di-(2 Ehtylhexyl)-Phtalate (DEHP) causes impaired adipocyte function and alters serum metabolites. PLoS One. 2015;10:e0143190.

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.

Haim Y, Blüher M, Slutsky N, Goldstein N, Klöting N, Harman-Boehm I, Kirshstein B, Ginsberg D, Gericke M, Guiu Jurado E, Kovsan J, Tarnovscki T, Kachko L, Bashan N, Gepner Y, Shai I, Rudich A. Elevated autophagy gene expression in adipose tissue of humans: A potential non-cell-cycle-dependent function of E2F1. Autophagy. 2015;11:2074-88.

Kralisch S, Klöting N, Ebert T, Kern M, Hoffmann A, Krause K, Jessnitzer B, Lossner U, Sommerer I, Stumvoll M, Fasshauer M. Circulating adipocyte fatty acid-binding protein induces insulin-resistance in mice in vivo. Obesity (Silver Spring). 2015;23:1007-13.

Hesselbarth N, Petinelli C, Gericke M, Berger C, Kunath A, Stumvoll M, Blüher M, Klöting N. Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice. Biochem Biophys Res Commun. 2015;464:724-9.

Lakowa N, Trieu N, Flehmig G, Lohmann T, Schön MR, Dietrich A, Zeplin PH, Langer S, Stumvoll M, Blüher M, Klöting N. Telomere length differences between subcutaneous and visceral adipose tissue in humans. Biochem Biophys Res Commun. 2015;457:426-32

Kannt A, Pfenniger A, Teichert L, Tönjes A, Dietrich A, Schön MR, Klöting N, Blüher M. Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance. Diabetologia. 2015;58:799-808.

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.

Cottilard A, Poitou C, Torcivia A, Bouillot JL, Dietrich A, Klöting N, Gregoire C, Lolmede K, Blüher M, Clement K. Adipocyte size treshold matters: link with risk of type 2 diabetes and improved insulin-resistance after gastric bypass. J Clin Endocrinol Metab. 2014;99:E1466-70.

Haase J, Weyer U, Immig K, Klöting N, Blüher M, Eilers J, Bechmann I, Gericke M. Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia. 2014;56:262-71.

Blüher MKlöting N, Wueest S, Schoenle EJ, Schön MR, Dietrich A, Fasshauer MStumvoll M, Konrad D. Fas and FasL Expression in Human Adipose Tissue Is Related to Obesity, Insulin Resistance, and Type 2 Diabetes. J Clin Endocrinol Metab. 2014;99:E36-44.

Schleinitz D, Klöting N, Lindgren CM, Breitfeld J, Dietrich A, Schön MR, Lohmann T, Dreßler M, Stumvoll M, McCarthy MI, Blüher M, Kovacs P. Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio. Int J Obes (Lond). 2014;38:120-5.

Hoffmeister A, Tuennemann J, Sommerer I, Mössner J, Rittger A, Schleinitz D, Kratzsch J, Rosendahl J, Klöting N, Stahl T, Rossner S, Paroni F, Maedler K, Kovacs P, Blüher M. Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression. Obesity (Silver Spring). 2013;21:E626-33.

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 mRNA expression is related to human obesity. Obesity (Silver Spring). 2013;21:529-34.

Krist J, Wieder K, Klöting N, Oberbach A, Kralisch S, Wiesner T, Schön MR, Gärtner D, Dietrich A, Shang E, Lohmann T, Dreßler M, Fasshauer M, Stumvoll M, Blüher M. Effects of weight loss and exercise on apelin serum concentrations and adipose tissue expression in human obesity. Obes Facts. 2013;6:57-69.

Sell H, Blüher M, Klöting N, Schlich R, Willems M, Ruppe F, Knoefel WT, Dietrich A, Fielding BA, Arner P, Frayn KN, Eckel J. Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care. 2013;36:4083-90.

Kosacka J, Nowicki M, Blüher M, Baum P, Stockinger M, Toyka KV, Klöting I, Stumvoll M, Serke H, Bechmann I, Klöting N. Increased autophagy in peripheral nerves may protect Wistar Ottawa Karlsburg W rats against neuropathy. Exp Neurol. 2013;250:125-35.

Heiker JT, Klöting N. Replication initiator 1 in adipose tissue function and human obesity.Vitam Horm. 2013;91:97-105.

Bahr J, Klöting N, Klöting I, Follak N. Gene expression profliling supports the role of Repin1 in the pathophysiology of metabolic syndrome. Endocrine. 2011; 40: 310-4.

Klöting N, Kovacs P, Kern M, Heiker JT, Fasshauer M, Schön MR, Stumvoll M, Blüher M. Central vaspin administration acutely reduces food intake and has sustained blood glucose-lowering effects. Diabetologia. 2011; 54:1819-23.

Ruschke K, Illes M, Kern M, Klöting I, Fasshauer M, Schön MR, Kosacka J, Fitzl G, Kovacs P, Stumvoll M, Blüher M, Klöting N. Repin1 maybe involved in the regulation of cell size and glucose transport in adipocytes. Biochem Biophys Res Commun. 2010; 400: 246-51.

Klöting N, Wilke B, Klöting I. Triplet repeat in the Repin 1 3'-untranslated region on rat chromosome 4 correlates with facets of the metabolic syndrome. Diabetes Metab Res Rev. 2007; 23: 406-10.


Claudia Berger, PhD student