1. Research Background:

The Central Nervous System (CNS) is constantly instructed about the energy state of the organism via hormonal andnutritional signals. It then coordinately regulates a wide array of behavioral and autonomic responses to adapt energyintake, 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, whichare on an epidemic rise in industrialized societies. The overall aim of our research group is to unravel the fundamentalregulatory principles of how neurons sense nutritional cues and then to determine the neurocircuitry responsible for thecoordinated adaptation of behavioral 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 organsim and how do they integrateanticipatory 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 multifacetted approach to address these key questions. First, we have employed state-of-the-arttechnologies in molecular systems neuroscience to identify molecularly defined neuronal populations in control of foodintake, systemic glucose homeostasis and related physiological processes. Second, we define the neurocircuitryarchitecture, how these cells integrate homeostatic and anticipatory signals. Third, we define the outcput circuitries,which ultimately execute communication with peripheral organs. Fourth, we define the molecular basis of disease-associated alterations in the activity of these neruociruits 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 neuroscricuits to prime orgamismal 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:

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• Jais A, Paeger L, Sotelo-Hitschfeld T, Bremser S, Prinzensteiner M, Klemm P, Mykytiuk V, Widdershooven PJM, Vesting AJ, Grzelka K, Minère M, Cremer AL, Xu J, Korotkova T, Lowell BB, Zeilhofer HU, Backes H, Fenselau H, Wunderlich FT, Kloppenburg P, Brüning JC. PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding. (2020)Neuron Apr 15:S0896-6273(20)30229-4. doi: 10.1016/j.neuron.2020.03.022.
• Engström Ruud L, Pereira MMA, de Solis AJ, Fenselau H, Brüning JC. NPY mediates the rapid feeding and glucosemetabolism regulatory functions of AgRP neurons. (2020) Nat Commun. Jan 23;11(1):442. doi: 10.1038/s41467-020-14291-3
• Hammerschmidt P, Ostkotte D, Nolte H, Gerl MJ, Jais A, Brunner HL, Sprenger HG, Awazawa M, Nicholls HT,Turpin-Nolan SM, Langer T, Krüger M, Brügger B, Brüning JC. CerS6-Derived Sphingolipids Interact with Mffand Promote Mitochondrial Fragmentation in Obesity. (2019) Cell May 30;177(6):1536-1552
• Brandt C, Nolte H, Henschke S, Engström Ruud L, Awazawa M, Morgan DA, Gabel P, Sprenger HG, Hess ME,Günther S, Langer T, Rahmouni K, Fenselau H, Krüger M, Brüning JC. Food Perception Primes Hepatic ER-Homeostasis via Melanocortin-Dependent Control of mTOR-Activation. (2018) Cell Nov 15;175(5):1321-1335.
• Jais A, Solas M, Backes H, Chaurasia B, Kleinridders A, Theurich S, Mauer J, Steculorum SM, Hampel B, Goldau J,Alber J, Förster CY, Eming SA, Schwaninger M, Ferrara N, Karsenty G, Brüning JC. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. (2016) Cell May 5; 165(4):882-895.
• Steculorum SM, Ruud J, Karakasilioti I, Backes H, Engström Ruud L, Timper K, Hess M, Tsaousidou E, Mauer J, VogtM.C, Paeger L, Bremser S, Klein AC, Morgan DA, Frommolt P, Brinkkötter PT, Benzing T, Rahmouni K, WunderlichT, Kloppenburg P, Brüning JC. AgRP-neurons control systemic insulin sensitivity via myostatin-expression inbrown- adipose tissue. (2016) Cell Mar 24;165(1):125-138.