1. Research Background:

The central nervous system (CNS) is constantly instructed about the energy state of the organism via hormonal and nutritional signals. It then co-ordinately regulates a wide array of behavioural and autonomic responses to adapt energy intake, energy expenditure, and nutrient flux across different organs, according to energy availability of the organism. Dysregulation of these homeostatic circuits causes prevalent diseases, such as obesity and type-2 diabetes mellitus, which are on an epidemic rise in industrialized societies. The overall aim of our research group is to unravel the fundamental regulatory principles of how neurons sense nutritional cues and then to determine the neurocircuitry responsible for the coordinated adaptation of behavioural and autonomic outputs. The ultimate aim of our research is to discover novel therapeutic targets for the development of treatment of metabolic disorders.

2. Research questions addresses by the group:

How are neurons in the hypothalamus instructed about the energy state of the organism and how do they integrate anticipatory signals of upcoming changes in energy state? 

How do neurons coordinate an integrative physiological response in accordance to changes in energy availability?

Our laboratory has taken a multifaceted approach to address these key questions. First, we have employed state-of-the-art technologies in molecular systems neuroscience to identify molecularly defined neuronal populations in control of food intake, systemic glucose homeostasis and related physiological processes. Second, we define the neurocircuitry architecture, how these cells integrate homeostatic and anticipatory signals. Third, we define the output circuitries, which ultimately execute communication with peripheral organs. Fourth, we define the molecular basis of disease-associated alterations in the activity of these neurocircuits as well as in peripheral target tissues.

3. Possible projects:

Some of the questions/projects we are pursuing include:

• How does the CNS regulate feeding responses?
• How does the CNS regulate peripheral glucose metabolism?
• How do fuel sensing neurons control proteostasis in peripheral tissues?
• How are anticipatory signals integrated in fuel sensing neurocircuits to prime organismal adaptation?
• What are the mechanisms of obesity- and ageing-associated de-regulation in these pathways?

4. Applied Methods and model organisms:

Model Organisms: Transgenic mouse models 

Methods: Genetics, Microscopy, Mass Spectrometry, Molecular Biology, Systems Biology (Transcriptomics, Proteomics, Metabolomics), Biochemistry, Molecular Systems Neuroscience, Optogenetics, Ca-Imaging in vivo.

5. Desirable skills and qualifications:

Neuroscience, Molecular Biology and Genetics

6. References:

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 Metabolism 35(5):786-806.e13. doi: 10.1016/j.cmet.2023.03.019. 

De Solis AJ*, Del Río-Martín A*, Radermacher J, Chen W, Steuernagel L, Bauder CA, Eggersmann FR, Morgan DA, Cremer AL, Sué M, Germer M, Kukat C, Vollmar S, Backes H, Rahmouni K, Kloppenburg P, Brüning JC (2024) Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism. Nature Metabolism 6(3):473-493. doi: 10.1038/s42255-024-00987-z. 

Del Río-Martín A, Yeghiazaryan G, de Oliveira Beleza R, Henschke S, Solheim MH, Mirabella PN, Sotelo-Hitschfeld T, Bauder CA, Jiang H, Chen W, Klemm P, Steuernagel L, de Solís AJ, Hammerschmidt P, Fenselau H, Wunderlich FT, Kloppenburg P, Brüning JC (2026) Mitochondrial fission factor regulates mitochondrial Ca²⁺ homeostasis and neuronal activity in AgRP neurons. Neuron 1:S0896-6273(26)00268-0. doi: 10.1016/j.neuron.2026.03.038. 

Dodt S, Widdershooven NV, Dreisow ML, Weiher L, Steuernagel L, Wunderlich FT, Brüning JC^#, Fenselau H^# (2024) NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation. Nature Communication 15(1):5439. doi: 10.1038/s41467-024-49766-0. 

Gaziano I, Corneliussen S, Biglari N, Neuhaus R, Shen L, Sotelo-Hitschfeld T, Klemm P, Steuernagel L, De Solis AJ, Chen W, Wunderlich FT, Kloppenburg P, Brüning JC (2022) Dopamine-inhibited POMC^Drd2+ neurons in the ARC acutely regulate feeding and body temperature. JCI Insight 7(21):e162753. doi: 10.1172/jci.insight.162753. 

Hammerschmidt P, Steculorum SM, Bandet CL, Del Río-Martín A, Steuernagel L, Kohlhaas V, Feldmann M, Varela L, Majcher A, Quatorze Correia M, Klar RFU, Bauder CA, Kaya E, Porniece M, Biglari N, Sieben A, Horvath TL, Hornemann T, Brodesser S, Brüning JC (2023) CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nature Communication 14(1):7824. doi: 10.1038/s41467-023-42595-7. 

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 MFF^S131 and mitochondrial fragmentation in liver. Science 384(6694):438-446. doi: 10.1126/science.adk1005. 

Izawa S, Fusca D, Jiang H, Heilinger C, Hausen AC, Wunderlich FT, Steuernagel L, Kloppenburg P, Brüning JC (2025) Orexin/hypocretin receptor 2 signaling in MCH neurons regulates REM sleep and insulin sensitivity. Cell Reports 44(2):115277. doi:10.1016/j.celrep.2025.115277.

Solheim MH, Stroganov S, Chen W, Subagia PS, Bauder CA, Wnuk-Lipinski D, Del Río-Martín A, Sotelo-Hitschfeld T, Beddows CA, Klemm P, Dodd GT, Lundh S, Secher A, Wunderlich FT, Steuernagel L, Brüning JC (2025) Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis. Cell 188(13):3550-3566.e22. doi: 10.1016/j.cell.2025.04.001. 

Sotelo-Hitschfeld T, Minère M, Klemm P, Borgmann D, Wnuk-Lipinski D, Jais A, Jia X, Corneliussen S, Kloppenburg P, Fenselau H, Brüning JC (2024) GABAergic disinhibition from the BNST to PNOC^ARC neurons promotes HFD-induced hyperphagia. Cell Reports 43(6):114343. doi: 10.1016/j.celrep.2024.114343.

Steuernagel L*, Lam BYH*, Klemm P, Dowsett GKC, Bauder CA, Tadross JA, Hitschfeld TS, Del Rio Martin A, Chen W, de Solis AJ, Fenselau H, Davidsen P, Cimino I, Kohnke SN, Rimmington D, Coll AP, Beyer A, Yeo GSH^#, Brüning JC^# (2022) HypoMap-a unified single-cell gene expression atlas of the murine hypothalamus. Nature Metabolism 4(10):1402-1419. doi: 10.1038/s42255-022-00657-y. 

Tadross JA*, Steuernagel L*, Dowsett GKC*, Kentistou KA, Lundh S, Porniece M, Klemm P, Rainbow K, Hvid H, Kania K, Polex-Wolf J, Knudsen LB, Pyke C, Perry JRB, Lam BYH, Brüning JC^#, Yeo GSH^# (2025) A comprehensive spatio-cellular map of the human hypothalamus. Nature 639(8055):708-716. doi: 10.1038/s41586-024-08504-8. 

Zhu Y, Mehlkop O, Backes H, Cremer AL, Porniece M, Klemm P, Steuernagel L, Chen W, Johnen R, Wunderlich FT, Jais A, Brüning JC (2025) Reduced Notch signaling in hypothalamic endothelial cells mediates obesity-induced alterations in glucose uptake and insulin signaling. Cell Reports 44(4):115522. doi: 10.1016/j.celrep.2025.115522. 

* joint first authors; # joint corresponding authors