Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to 
whole-body metabolism

Hausl, Alexander S.; Bajaj, Thomas; Brix, Lea; Pohlmann, Max L.; Hafner, Kathrin; De Angelis, Meri; Nagler, Joachim; Dethloff, Frederik; Balsevich, Georgia; Schramm, Karl-Werner; Giavalisco, Patrick; Chen, Alon; Schmidt, Mathias V.; Gassen, Nils C.

doi:10.1126/sciadv.abi4797

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Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism

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Hausl, Alexander S.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

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Brix, Lea
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Pohlmann, Max L.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

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Hafner, Kathrin
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Balsevich, Georgia
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons129892

Chen, Alon
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Schmidt, Mathias V.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

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Gassen, Nils C.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Hausl, A. S., Bajaj, T., Brix, L., Pohlmann, M. L., Hafner, K., De Angelis, M., et al. (2022). Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. SCIENCE ADVANCES, 8(10): eabi4797. doi:10.1126/sciadv.abi4797.

Cite as: https://hdl.handle.net/21.11116/0000-000A-6AA4-6

Abstract

The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1 /AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD)-induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.