@article{HesseJaschkeKanzleiteretal.2012, author = {Hesse, Deike and Jaschke, Alexander and Kanzleiter, Timo and Witte, Nicole and Augustin, Robert and Hommel, Angela and P{\"u}schel, Gerhard Paul and Petzke, Klaus-J{\"u}rgen and Joost, Hans-Georg and Schupp, Michael and Sch{\"u}rmann, Annette}, title = {GTPase ARFRP1 is essential for normal hepatic glycogen storage and insulin-like growth factor 1 secretion}, series = {Molecular and cellular biology}, volume = {32}, journal = {Molecular and cellular biology}, number = {21}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0270-7306}, doi = {10.1128/MCB.00522-12}, pages = {4363 -- 4374}, year = {2012}, abstract = {The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50\% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage.}, language = {en} } @article{MuenznerTuviaDeutschmannetal.2013, author = {M{\"u}nzner, Matthias and Tuvia, Neta and Deutschmann, Claudia and Witte, Nicole and Tolkachov, Alexander and Valai, Atijeh and Henze, Andrea and Sander, Leif E. and Raila, Jens and Schupp, Michael}, title = {Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor alpha activity}, series = {Molecular and cellular biology}, volume = {33}, journal = {Molecular and cellular biology}, number = {20}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0270-7306}, doi = {10.1128/MCB.00221-13}, pages = {4068 -- 4082}, year = {2013}, abstract = {Retinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo-and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RAR alpha activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RAR alpha signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RAR alpha. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RAR alpha activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RAR alpha activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinoldependent metabolic function of RBP4 that may have important implications for the treatment of obesity.}, language = {en} } @article{HorikoshiYaghootkarMookKanamorietal.2013, author = {Horikoshi, Momoko and Yaghootkar, Hanieh and Mook-Kanamori, Dennis O. and Sovio, Ulla and Taal, H. Rob and Hennig, Branwen J. and Bradfield, Jonathan P. and St Pourcain, Beate and Evans, David M. and Charoen, Pimphen and Kaakinen, Marika and Cousminer, Diana L. and Lehtimaki, Terho and Kreiner-Moller, Eskil and Warrington, Nicole M. and Bustamante, Mariona and Feenstra, Bjarke and Berry, Diane J. and Thiering, Elisabeth and Pfab, Thiemo and Barton, Sheila J. and Shields, Beverley M. and Kerkhof, Marjan and van Leeuwen, Elisabeth M. and Fulford, Anthony J. and Kutalik, Zoltan and Zhao, Jing Hua and den Hoed, Marcel and Mahajan, Anubha and Lindi, Virpi and Goh, Liang-Kee and Hottenga, Jouke-Jan and Wu, Ying and Raitakari, Olli T. and Harder, Marie N. and Meirhaeghe, Aline and Ntalla, Ioanna and Salem, Rany M. and Jameson, Karen A. and Zhou, Kaixin and Monies, Dorota M. and Lagou, Vasiliki and Kirin, Mirna and Heikkinen, Jani and Adair, Linda S. and Alkuraya, Fowzan S. and Al-Odaib, Ali and Amouyel, Philippe and Andersson, Ehm Astrid and Bennett, Amanda J. and Blakemore, Alexandra I. F. and Buxton, Jessica L. and Dallongeville, Jean and Das, Shikta and de Geus, Eco J. C. and Estivill, Xavier and Flexeder, Claudia and Froguel, Philippe and Geller, Frank and Godfrey, Keith M. and Gottrand, Frederic and Groves, Christopher J. and Hansen, Torben and Hirschhorn, Joel N. and Hofman, Albert and Hollegaard, Mads V. and Hougaard, David M. and Hyppoenen, Elina and Inskip, Hazel M. and Isaacs, Aaron and Jorgensen, Torben and Kanaka-Gantenbein, Christina and Kemp, John P. and Kiess, Wieland and Kilpelainen, Tuomas O. and Klopp, Norman and Knight, Bridget A. and Kuzawa, Christopher W. and McMahon, George and Newnham, John P. and Niinikoski, Harri and Oostra, Ben A. and Pedersen, Louise and Postma, Dirkje S. and Ring, Susan M. and Rivadeneira, Fernando and Robertson, Neil R. and Sebert, Sylvain and Simell, Olli and Slowinski, Torsten and Tiesler, Carla M. T. and Toenjes, Anke and Vaag, Allan and Viikari, Jorma S. and Vink, Jacqueline M. and Vissing, Nadja Hawwa and Wareham, Nicholas J. and Willemsen, Gonneke and Witte, Daniel R. and Zhang, Haitao and Zhao, Jianhua and Wilson, James F. and Stumvoll, Michael and Prentice, Andrew M. and Meyer, Brian F. and Pearson, Ewan R. and Boreham, Colin A. G. and Cooper, Cyrus and Gillman, Matthew W. and Dedoussis, George V. and Moreno, Luis A. and Pedersen, Oluf and Saarinen, Maiju and Mohlke, Karen L. and Boomsma, Dorret I. and Saw, Seang-Mei and Lakka, Timo A. and Koerner, Antje and Loos, Ruth J. F. and Ong, Ken K. and Vollenweider, Peter and van Duijn, Cornelia M. and Koppelman, Gerard H. and Hattersley, Andrew T. and Holloway, John W. and Hocher, Berthold and Heinrich, Joachim and Power, Chris and Melbye, Mads and Guxens, Monica and Pennell, Craig E. and Bonnelykke, Klaus and Bisgaard, Hans and Eriksson, Johan G. and Widen, Elisabeth and Hakonarson, Hakon and Uitterlinden, Andre G. and Pouta, Anneli and Lawlor, Debbie A. and Smith, George Davey and Frayling, Timothy M. and McCarthy, Mark I. and Grant, Struan F. A. and Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta and Timpson, Nicholas J. and Prokopenko, Inga and Freathy, Rachel M.}, title = {New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism}, series = {Nature genetics}, volume = {45}, journal = {Nature genetics}, number = {1}, publisher = {Nature Publ. Group}, address = {New York}, organization = {MAGIC, Early Growth Genetics EGG}, issn = {1061-4036}, doi = {10.1038/ng.2477}, pages = {76 -- U115}, year = {2013}, abstract = {Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.}, language = {en} }