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

Philipp Hammerschmidt, Sophie M. Steculorum, Cécile L. Bandet, Almudena Río-Martín, Lukas Steuernagel, Vivien Kohlhaas, Marvin Feldmann, Luis Varela, Adam Majcher, Marta Quatorze Correia, Rhena F. U. Klar, Corinna A. Bauder, Ecem Kaya, Marta Porniece, Nasim Biglari, Anna Sieben, Tamas L. Horvath, Thorsten Hornemann, Susanne Brodesser and Jens C. Brüning ()
Additional contact information
Philipp Hammerschmidt: Max Planck Institute for Metabolism Research
Sophie M. Steculorum: University of Cologne
Cécile L. Bandet: Max Planck Institute for Metabolism Research
Almudena Río-Martín: Max Planck Institute for Metabolism Research
Lukas Steuernagel: Max Planck Institute for Metabolism Research
Vivien Kohlhaas: Max Planck Institute for Metabolism Research
Marvin Feldmann: Max Planck Institute for Metabolism Research
Luis Varela: Yale University School of Medicine, 310 Cedar St., BML 330
Adam Majcher: University of Zürich
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
Ecem Kaya: Max Planck Institute for Metabolism Research
Marta Porniece: Max Planck Institute for Metabolism Research
Nasim Biglari: Max Planck Institute for Metabolism Research
Anna Sieben: Max Planck Institute for Metabolism Research
Tamas L. Horvath: University of Cologne
Thorsten Hornemann: University of Zürich
Susanne Brodesser: University of Cologne
Jens C. Brüning: Max Planck Institute for Metabolism Research

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42595-7

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