Identification of ALK in Thinness

Michael Orthofer¹, Armand Valsesia², Reedik Mägi³, Qiao-Ping Wang⁴, Joanna Kaczanowska⁵, Ivona Kozieradzki¹, Alexandra Leopoldi¹, Domagoj Cikes¹, Lydia M Zopf⁶, Evgenii O Tretiakov⁷, Egon Demetz⁸, Richard Hilbe⁸, Anna Boehm⁸, Melita Ticevic¹, Margit Nõukas³, Alexander Jais⁹, Katrin Spirk¹⁰, Teleri Clark¹¹, Sabine Amann⁹, Maarja Lepamets³, Christoph Neumayr⁵, Cosmas Arnold⁵, Zhengchao Dou¹², Volker Kuhn⁸, Maria Novatchkova⁵, Shane J F Cronin¹, Uwe J F Tietge¹³, Simone Müller¹⁴, J Andrew Pospisilik¹⁵, Vanja Nagy¹⁶, Chi-Chung Hui¹², Jelena Lazovic⁶, Harald Esterbauer⁹, Astrid Hagelkruys¹, Ivan Tancevski⁸, Florian W Kiefer¹⁰, Tibor Harkany¹⁷, Wulf Haubensak⁵, G Gregory Neely¹¹, Andres Metspalu³, Jorg Hager¹⁸, Nele Gheldof¹⁹, Josef M Penninger²⁰

Affiliations

¹ IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
² Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland.
³ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
⁴ School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
⁵ IMP, Institute of Molecular Pathology, Vienna 1030, Austria.
⁶ Vienna BioCenter Core Facilities GmbH (VBCF), Vienna 1030, Austria.
⁷ Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria.
⁸ Department of Internal Medicine II, Innsbruck Medical University, Innsbruck 6020, Austria.
⁹ Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria.
¹⁰ Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna 1090, Austria.
¹¹ Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia.
¹² Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹³ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 141 52 Huddinge, Sweden; Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, 141 86 Stockholm, Sweden.
¹⁴ Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
¹⁵ Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁶ Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria.
¹⁷ Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria; Section for Chemical Neurotransmission, Department of Neuroscience, Biomedicum 7D, Solnavägen 9, 17165 Solna, Sweden.
¹⁸ Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland. Electronic address: jorg.hager@rd.nestle.com.
¹⁹ Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland. Electronic address: nele.gheldof@rd.nestle.com.
²⁰ IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria; Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: josef.penninger@ubc.ca.

PMID: 32442405
DOI: 10.1016/j.cell.2020.04.034

Free article

Identification of ALK in Thinness

Michael Orthofer et al. Cell. 2020.

Free article

. 2020 Jun 11;181(6):1246-1262.e22.

doi: 10.1016/j.cell.2020.04.034. Epub 2020 May 21.

Authors

Affiliations

¹ IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
² Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland.
³ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
⁴ School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
⁵ IMP, Institute of Molecular Pathology, Vienna 1030, Austria.
⁶ Vienna BioCenter Core Facilities GmbH (VBCF), Vienna 1030, Austria.
⁷ Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria.
⁸ Department of Internal Medicine II, Innsbruck Medical University, Innsbruck 6020, Austria.
⁹ Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria.
¹⁰ Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna 1090, Austria.
¹¹ Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, Centenary Institute, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia.
¹² Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹³ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 141 52 Huddinge, Sweden; Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, 141 86 Stockholm, Sweden.
¹⁴ Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
¹⁵ Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁶ Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090 Vienna, Austria.
¹⁷ Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria; Section for Chemical Neurotransmission, Department of Neuroscience, Biomedicum 7D, Solnavägen 9, 17165 Solna, Sweden.
¹⁸ Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland. Electronic address: jorg.hager@rd.nestle.com.
¹⁹ Metabolic Phenotyping, Nestlé Research, EPFL Innovation Park, Lausanne 1015, Switzerland. Electronic address: nele.gheldof@rd.nestle.com.
²⁰ IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria; Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: josef.penninger@ubc.ca.

PMID: 32442405
DOI: 10.1016/j.cell.2020.04.034

Abstract

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6^th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.

Keywords: GWAS; anaplastic lymphoma kinase; energy expenditure; hypothalamus; lipolysis; norepinephrine; thinness.

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Conflict of interest statement

Declaration of Interests J.H., N.G., and A.V. are employed by Nestlé Research. J.H., N.G., and A.V. have filed a patent on Methods of Modulating ALK (WO2019101490).

Comment in

Deciphering the genetics of resistance to weight gain.
Greenhill C. Greenhill C. Nat Rev Endocrinol. 2020 Aug;16(8):403. doi: 10.1038/s41574-020-0376-2. Nat Rev Endocrinol. 2020. PMID: 32483325 No abstract available.
Constitutional Thinness: tALKing the tALK or wALKing the wALK?
Tung YCL, O'Rahilly S. Tung YCL, et al. Cell Metab. 2020 Jul 7;32(1):8-10. doi: 10.1016/j.cmet.2020.06.012. Cell Metab. 2020. PMID: 32640247

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Identification of ALK in Thinness

Affiliations

Identification of ALK in Thinness

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

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