DEP-1 is a brain insulin receptor phosphatase that prevents the simultaneous activation of counteracting metabolic pathways
Simran Chopra,
Otsuware Linda-Josephine Kadiri,
Jannis Ulke,
Robert Hauffe,
Wenke Jonas,
Sahar Cheshmeh,
Luisa Schmidt,
Christopher A. Bishop,
Selma Yagoub,
Mareike Schell,
Michaela Rath,
Janine Krüger,
Rachel N. Lippert,
Marcus Krüger,
Kai Kappert,
André Kleinridders
Affiliations
Simran Chopra
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
Otsuware Linda-Josephine Kadiri
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
Jannis Ulke
Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Cardiovascular-Metabolic-Renal (CMR) Research Center, Charité – Universitätsmedizin Berlin, Hessische Straße 3–4, 10115 Berlin, Germany
Robert Hauffe
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
Wenke Jonas
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
Sahar Cheshmeh
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
Luisa Schmidt
Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
Christopher A. Bishop
Department Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
Selma Yagoub
Department of Neurocircuit, Development and Function, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
Mareike Schell
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
Michaela Rath
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany
Janine Krüger
Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Cardiovascular-Metabolic-Renal (CMR) Research Center, Charité – Universitätsmedizin Berlin, Hessische Straße 3–4, 10115 Berlin, Germany
Rachel N. Lippert
German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany; Department of Neurocircuit, Development and Function, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany; NeuroCure Cluster of Excellence, Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany
Marcus Krüger
Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany
Kai Kappert
Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Cardiovascular-Metabolic-Renal (CMR) Research Center, Charité – Universitätsmedizin Berlin, Hessische Straße 3–4, 10115 Berlin, Germany
André Kleinridders
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; Corresponding author
Summary: A healthy metabolism relies on precise regulation of anabolic and catabolic pathways. While insulin deficiency impairs anabolism, insulin resistance in obesity causes metabolic dysfunction, especially via altered brain insulin receptor (IR) activity. Density-enhanced phosphatase 1 (DEP-1) negatively modulates the IR in peripheral tissues. Our study shows that DEP-1 is an insulin-regulated gene, dysregulated in obesity, and uncovers its role in brain insulin signaling, impacting both anabolic and catabolic pathways. Neuro-2a cells lacking DEP-1 demonstrated heightened IR phosphorylation upon acute insulin stimulation. This coincided with simultaneous AMP-activated protein kinase (AMPK) activation, which governs catabolic pathways, due to increased phospholipase C-gamma 1 signaling. These opposing pathways in male DEP-1 forebrain-specific knockout mice resulted in elevated lipolysis in white adipose tissue and fat oxidation in brown adipose tissue, with enhanced sympathetic activation and β-adrenergic receptor expression. In conclusion, DEP-1 deficiency causes the simultaneous activation of IR and AMPK signaling in the brain, with enhanced sympathetic activity in adipose tissues.
