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CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice

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Listed:
  • Philipp Hammerschmidt

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Sophie M. Steculorum

    (University of Cologne
    Max Planck Institute for Metabolism Research, Research Group Neurocircuit Wiring and Function
    National Center for Diabetes Research (DZD))

  • Cécile L. Bandet

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Almudena Río-Martín

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Lukas Steuernagel

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Vivien Kohlhaas

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Marvin Feldmann

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne
    University of Cologne)

  • Luis Varela

    (Yale University School of Medicine, 310 Cedar St., BML 330
    Laboratory of Glia-Neuron Interactions in the Control of Hunger. Achucarro Basque Center for Neuroscience
    Ikerbasque-Basque Foundation for Science)

  • Adam Majcher

    (University of Zürich
    University Hospital)

  • Marta Quatorze Correia

    (Max Planck Institute for Metabolism Research)

  • Rhena F. U. Klar

    (Max Planck Institute for Metabolism Research)

  • Corinna A. Bauder

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Ecem Kaya

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Marta Porniece

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Nasim Biglari

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Anna Sieben

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne)

  • Tamas L. Horvath

    (University of Cologne
    Yale University School of Medicine, 310 Cedar St., BML 330
    Laboratory of Glia-Neuron Interactions in the Control of Hunger. Achucarro Basque Center for Neuroscience
    Ikerbasque-Basque Foundation for Science)

  • Thorsten Hornemann

    (University of Zürich
    University Hospital)

  • Susanne Brodesser

    (University of Cologne)

  • Jens C. Brüning

    (Max Planck Institute for Metabolism Research
    Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne
    University of Cologne
    National Center for Diabetes Research (DZD))

Abstract

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

Suggested Citation

  • Philipp Hammerschmidt & Sophie M. Steculorum & Cécile L. Bandet & Almudena Río-Martín & Lukas Steuernagel & Vivien Kohlhaas & Marvin Feldmann & Luis Varela & Adam Majcher & Marta Quatorze Correia & Rh, 2023. "CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42595-7
    DOI: 10.1038/s41467-023-42595-7
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    References listed on IDEAS

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    1. Thangaselvam Muthusamy & Thekla Cordes & Michal K. Handzlik & Le You & Esther W. Lim & Jivani Gengatharan & Antonio F. M. Pinto & Mehmet G. Badur & Matthew J. Kolar & Martina Wallace & Alan Saghatelia, 2020. "Serine restriction alters sphingolipid diversity to constrain tumour growth," Nature, Nature, vol. 586(7831), pages 790-795, October.
    2. Johan Ruud & Sophie M. Steculorum & Jens C. Brüning, 2017. "Neuronal control of peripheral insulin sensitivity and glucose metabolism," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    3. Nigel Turner & Xin Ying Lim & Hamish D. Toop & Brenna Osborne & Amanda E. Brandon & Elysha N. Taylor & Corrine E. Fiveash & Hemna Govindaraju & Jonathan D. Teo & Holly P. McEwen & Timothy A. Couttas &, 2018. "A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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