UNIVERSITÄT ZU KÖLN

Jens Brüning
Max Planck Institute for Metabolism Research
Cologne

Phone: +49 221 / 4726 202       
E-mail: Brueningsf.mpg.de
For more information and contact please visit the BRÜNING LAB

Running time within the CRC 1218: 07/2016 - 06/2028.
From 2016-2020 together with Tamas Horvath, Yale University, Department of Comparative Medicine, New Haven, CT; for more information and contact please visit the HORVATH LAB.

Abstract

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states. During the last funding period, we showed that sensory food perception rapidly induces mitochondrial fission in the liver via protein kinase B/AKT-dependent phosphorylation of the mitochondrial fission factor (MFFS131), a response mediated via activation of hypothalamic Pro-opiomelanocortin (POMC)-expressing neurons. We aim now to elucidate the molecular basis of how MFF-dependent mitochondrial fragmentation dynamically regulates gluconeogenesis in liver through detailed metabolomic flux analyses in cultured hepatocytes and mice in vivo. Moreover, the proposed studies aim to define liver-derived signalling mediators as well as their neuronal targets.
 

Project-related publications

Henschke S, Nolte H, Magoley J, Kleele T, Brandt C, Hausen AC, Wunderlich CM, Bauder CA, Aschauer P, Manley S, Langer T, Wunderlich FT, Brüning JC. (2024). Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver. Science 384(6694):438-446. DOI: 10.1126/science.adk1005.

Chen W, Mehlkop O, Scharn A, Nolte H, Klemm P, Henschke S, Steuernagel L, Sotelo-Hitschfeld T, Kaya E, Wunderlich CM, Langer T, Kononenko NL, Giavalisco P, Brüning JC (2023). Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation. Cell Metab 35:786-806.e713. DOI: 10.1016/j.cmet.2023.03.019.

Biglari N, Gaziano I, Schumacher J, Radermacher J, Paeger L, Klemm P, Chen W, Corneliussen S, Wunderlich CM, Sue M, Vollmar S, Klockener T, Sotelo-Hitschfeld T, Abbasloo A, Edenhofer F, Reimann F, Gribble FM, Fenselau H, Kloppenburg P, Wunderlich FT, Bruning JC (2021). Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nat Neurosci 24:913-929. DOI: 10.1038/s41593-021-00854-0.

Willenborg, S., Sanin, D.E., Jais, A., Ding, X., Ulas, T., Nüchel, J., Popović, M., MacVicar, T., Langer, T., Schultze, J.L., Gerbaulet, A., Roers, A., Pearce, E.J., Brüning, J.C., Trifunovic, A., Eming, S.A. (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing.  Cell Metabolism (2021), https://doi.org/10.1016/j.cmet.2021.10.004

Aravamudhan, S., Türk, C., Bock, T., Keufgens, L., Nolte, H., Lang, F., Krishnan, R.K., König, T., Hammerschmidt, P., Schindler, N., Brodesser, S., Rozsivalova, D.H., Rugarli, E., Trifunovic, A., Brüning, J., Langer, T., Braun, T., Krüger, M. (2021). Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein.  2021 Feb 5;154:41-59. doi.org/10.1016/j.yjmcc.2021.01.010

Timper, K., del Río-Martín, A., Cremer, A.L., Bremser, S., Alber, J. Giavalisco, P. Varela, L., Heilinger, C., Nolte, H., Trifunovic, A. Horvath, T.L., Kloppenburg, P., Backes, H. Brüning, J.C.  (2020). GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function. Cell Metab. S1550-4131(20)30240-0. doi: 10.1016/j.cmet.2020.05.001. Online ahead of print.

Hammerschmidt, P., Ostkotte, D., Nolte, H., Gerl, M.J., Jais, A., Brunner, H.L., Sprenger, H.G., Awazawa, M., Nicholls, H.T., Turpin-Nolan, S.M., Langer, T., Krüger, M., Brügger, B., and Brüning, J.C. (2019). CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity. Cell 177, 1536-1552.

Raichur, S., Brunner, B., Bielohuby, M., Hansen, G., Pfenninger, A., Wang, B., Brüning, J.C., Larsen, P.J., and Tennagels, N. (2019). The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach. Mol. Metab. 21, 36-50.

Turpin-Nolan, S.M., Hammerschmidt, P., Chen, W., Jais, A., Timper, K., Awazawa, M., Brodesser, S., and Brüning, J.C. (2019). CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance. Cell Rep. 26, 1-10.

Timper, K., Paeger, L., Sánchez-Lasheras, C., Varela, L., Jais, A., Nolte, H., Vogt, M.C., Hausen, A.C., Heilinger, C., Evers, N., Pospisilik, J.A., Penninger, J.M., Taylor, E.B., Horvath, T.L., Kloppenburg, P., Brüning, J.C.. (2018). Mild impairment of mitochondrial OXPHOS promotes fatty acid utilization in POMC neurons and improves glucose homeostasis in obesity. Cell Rep. 25, 383-397.

Brandt, C., Nolte, H., Henschke, S., Engström, Ruud, L., Awazawa, M., Morgan, D.A., Gabel, P., Sprenger, H.G., Hess, M.E., Günther, S., Langer, T., Rahmouni, K., Fenselau, H., Krüger, M., and Brüning, J.C. (2018). Food Perception Primes Hepatic ER-Homeostasis via Melanocortin-Dependent Control of mTOR-Activation. (2018) Cell Nov 15;175, 1321-1335.

Steculorum S.M., Paeger, L., Bremser, S., Evers, N., Hinze, Y., Idzko, M., Kloppenburg, P., and Brüning, J.C. (2015). Hypothalamic UDP increases in obesity and promotes feeding via P2Y6-dependent activation of AgRP-neurons. Cell 162, 1404-1417.

Dietrich, M.O., Zimmer, M.R., Bober, J., and Horvath, T.L. (2015). Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160, 1222-1232.