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Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.
Sci Adv. 2022 03 11; 8(10):eabi4797.SA

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.

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Authors+Show Affiliations

Häusl AS
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Bajaj T
Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127 Bonn, Germany.
Brix LM
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany. International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Kraepelinstr. 2-10, 80804 Munich, Germany.
Pöhlmann ML
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Hafner K
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
De Angelis M
Helmholtz Center Munich Germany Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.
Nagler J
Helmholtz Center Munich Germany Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.
Dethloff F
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Balsevich G
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Schramm KW
Helmholtz Center Munich Germany Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.
Giavalisco P
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Chen A
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Schmidt MV
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Gassen NC
Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127 Bonn, Germany. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.

MeSH

AutophagyDiet, High-FatHumansHypothalamusObesityTacrolimus Binding Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35263141

Citation

Häusl, Alexander S., et al. "Mediobasal Hypothalamic FKBP51 Acts as a Molecular Switch Linking Autophagy to Whole-body Metabolism." Science Advances, vol. 8, no. 10, 2022, pp. eabi4797.
Häusl AS, Bajaj T, Brix LM, et al. Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. Sci Adv. 2022;8(10):eabi4797.
Häusl, A. S., Bajaj, T., Brix, L. M., Pöhlmann, M. L., Hafner, K., De Angelis, M., Nagler, J., Dethloff, F., Balsevich, G., Schramm, K. W., Giavalisco, P., Chen, A., Schmidt, M. V., & Gassen, N. C. (2022). Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. Science Advances, 8(10), eabi4797. https://doi.org/10.1126/sciadv.abi4797
Häusl AS, et al. Mediobasal Hypothalamic FKBP51 Acts as a Molecular Switch Linking Autophagy to Whole-body Metabolism. Sci Adv. 2022 03 11;8(10):eabi4797. PubMed PMID: 35263141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. AU - Häusl,Alexander S, AU - Bajaj,Thomas, AU - Brix,Lea M, AU - Pöhlmann,Max L, AU - Hafner,Kathrin, AU - De Angelis,Meri, AU - Nagler,Joachim, AU - Dethloff,Frederik, AU - Balsevich,Georgia, AU - Schramm,Karl-Werner, AU - Giavalisco,Patrick, AU - Chen,Alon, AU - Schmidt,Mathias V, AU - Gassen,Nils C, Y1 - 2022/03/09/ PY - 2022/3/9/entrez PY - 2022/3/10/pubmed PY - 2022/4/20/medline SP - eabi4797 EP - eabi4797 JF - Science advances JO - Sci Adv VL - 8 IS - 10 N2 - 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. SN - 2375-2548 UR - https://www.unboundmedicine.com/medline/citation/35263141/Mediobasal_hypothalamic_FKBP51_acts_as_a_molecular_switch_linking_autophagy_to_whole_body_metabolism_ DB - PRIME DP - Unbound Medicine ER -