TRR 134:  Essverhalten: Homöostase und Belohnungssysteme

• Fachliche Zuordnung: Medizin ; Sozial- und Verhaltenswissenschaften
• Förderung: Förderung von 2014 bis 2018
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 222193485

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

The incidence and prevalence of obesity continues to rise and is particularly observed in populations exposed to an unprecedented abundance of food. Against this background, it represents an urgent task to unravel the central nervous mechanisms that act to integrate the homeostatic and rewardassociated neurocircuits encoding the behavioural portfolio relevant for food choice and intake. Consequently, it will be mandatory to search for an altered convergence of these two systems as the underlying basis for disturbed eating behaviour. To this end, we have defined fundamental principles of dysfunction in the pathogenesis of homeostatic versus reward driven obesity, namely (i) a disturbed processing of sensory signals, (ii) the loss of physiological function of satiety signals in the homeostatic system, (iii) a disturbed communication between reward and homeostatic systems with either insufficient inhibition of reward signals by homeostatic mechanisms or disinhibition of homeostatic signals by reward-associated stimulation and (iv) the tendency of reward-triggered food intake to eventually evolve into habitual behaviour. Within this concept, we have systematically moved towards a more system-based and translational research programme to decipher the interaction between homeostatic and reward circuits in a broader context with regards to neuronal and functional interactions (level A). The analysis of this crosstalk has also included relevant models of social interaction and cue triggered/external eating behaviour in a more clinically oriented translational context (level B). Clearly defined intervention strategies to enable tackling these problems through neuromodulation, pharmacological means or targeted neurosurgical approaches have been employed (level C). Finally, human studies within the CRC have benefitted from a pheno- and genotypically well-characterized cohort in the Z2 project. The recruitment of normal individuals and individuals which are environmentally or genetically prone to altered eating behaviour is clearly essential for the experimental paradigms and targeted interventions within this program. We anticipate conceptual advances for the whole research area in a long-term perspective. Based on the novel and mechanistic insight into the principles of convergence and regulation of the homeostatic and reward systems, thorough insight into the association between specific behavioural patterns and neural signals will be gained and will, by the aid of the cohort established, move our approaches towards a more targeted and precision medicine approach, which is needed for the treatment of obese persons. This CRC was (and with its scientific offsprings continues to be) embedded into a strong and focused research infrastructure at the participating universities and has received highest priority in terms of strategic planning and support. Moreover, the participating scientists have created a consortial and highly cooperative environment that will continue to build upon the complementary strengths and the joint and well-defined research focus.

Projektbezogene Publikationen (Auswahl)

• (2016). Insulin Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity. Cell Rep 17, 2512-2521
  Hausen, A.C., Ruud, J., Jiang, H., Hess, S., Varbanov, H., Kloppenburg, P., Brüning, J.C.
  
• (2017) Tanycytes control the hormonal output of the hypothalamic -pituitary-thyroid axis. Nat Commun 8, 484
  Müller-Fielitz H, Stahr M, Bernau M, Richter M, Abele S, Krajka V, Benzin A, Wenzel J, Kalies K, Mittag J, Heuer H, Offermanns S, Schwaninger M
  
• (2017). Analysis and correction of field fluctuations in fMRI using concurrent field monitoring. NeuroImage 154, 92-105
  Bollmann, S., Kasper, L., Vannesjo, SJ., Diaconescu, AO., Dietrich, BE., Gross, S., Stephan, KE., Pruess mann, KP.
  
• (2017). Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenalin. Elife. 2017 Jun 20;6
  Paeger L, Karakasilioti I, Altmüller J, Frommolt P, Brüning J, Kloppenburg P
  
• (2017). Central insulin modulates food valuation via mesolimbic pathways. Nature Communications 8, 16052
  Tiedemann, L.J., Schmid, S.M., Hettel, J., Giesen, K., Francke, P., Büchel, C., and Brassen, S.
  
• (2017). Effects of a 72 hours fasting on brain metabolism in healthy women studied in vivo with magnetic resonance spectroscopic imaging. J Cereb Blood Flow Metab. 38, 469-478
  Ding, X.Q., Maudsley, A.A., Schweiger, U., Schmitz, B., Lichtinghagen, R., Bleich, S., Lanfermann, H., and Kahl, K.G.
  
• (2017). Human subthalamic nucleus-automatic auditory change detection as a basis for action selection. Neuroscience 355, 141-148
  Heldmann, M., Münte, T.F., Paracka, L., Beyer, F., Brüggemann, N., Sarryeva, A., Rasche, D., Krauss, J.K., Tronnier, V.
  
• (2017). IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Reports 19, 267-280
  Timper, K., Denson, J.L., Steculorum, S.M., Heilinger, C., Engström-Ruud, L., Wunderlich, C.M., Rose- John, S., Wunderlich, F.T., and Brüning, J.C.
  
• (2017). Impact of nutrition on social decision making. Proc. Natl. Acad. Sci. USA. 114, 6510-6514
  Strang, S., Hoeber, C., Uhl, O., Koletzko, B., Münte, T.F., Lehnert, H., Dolan, R.J., Schmid, S.M., Park, S.Q.
  
• (2017). Inhibition of P2Y6 signaling in AgRP neurons reduces food intake and improves systemic insulin sensitivity in obesity. Cell Reports 18, 1587-1597
  Steculorum, S.M., Timper, K., Engström Ruud, L., Evers, N., Paeger, L., Bremser, S., Kloppenburg, P., and Brüning, J.C.
  
• (2017). Insulin controls food intake and energy balance via NPY neurons. Molecular Metabolism 6, 574-584
  Loh, K., Zhang, L., Brandon, A., Wang, Q., Begg, D., Qi, Y., Fu, M., Kulkarni, R., Teo, J., Baldock, P., et al.
  
• (2017). Key Odorants Regulate Food Attraction in Drosophila mela nogaster. Front Behav Neurosci. 5;11:160
  Giang T., He J., Belaidi S., Scholz H.
  
• (2017). Nesfatin-1: functions and physiology of a novel regulator peptide. J Endocrinol. 232, R45-R65
  Dore, R., Levata, L., Lehnert, H., Schulz, C.
  
• (2017). Prediction of individual differences from neuroimaging data. NeuroImage 145, 135-136
  Calhoun, VD., Lawrie, SM., Mourao-Miranda, J., Stephan, KE.
  
• (2017). The human globus pallidus internus is sensitive to rewards - Evidence from intracerebral recordings. Brain Stimul. 10, 657-663
  Münte, T.F., Marco-Pallares, J., Bolat, S., Heldmann, M., Lütjens, G., Nager, W., Müller-Vahl, K., Krauss, J.K.
  
• (2017). The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system. J Endocrinol. 235, 111-122
  Dore, R., Levata, L., Gachkar, S., Jöhren, O., Mittag, J., Lehnert, H., Schulz, C.
  
• (2017). Tissue-specific dissociation of diurnal transcriptome rhythms during sleep restriction in mice. Sleep 40
  Husse, J., Kiehn, J.-T., Barclay, J.L., Naujokat, N., Meyer-Kovac, J., Lehnert, H., and Oster, H.
  
• (2017). Transient Voltage Activated K+ Currents in central antennal lobe neurons: Cell type specific functional properties. J Neurophysiol 18, 1587-1597
  Paeger L, Bardos V, Kloppenburg P
  
• (2017). Visual food cues decrease post prandial glucose concentrations in lean and obese men without affecting food intake and related endocrine parameters. Appetite 117, 255-262
  Brede, S., Sputh, A., Hartmann, AC., Hallschmid, M., Lehnert, H., Klement, J.
  
• (2017): Oxytocin im proves β-Cell responsivity and glucose tolerance in healthy Men. Diabetes 66, 264-271
  Klement, J., Ott, V., Rapp, K., Brede, S., Piccinini, F., Cobelli, C., Lehnert, H., Hallschmid, M.
  
• (2018). Diet-induced growth is regulated via acquired lep tin resistance and engages a POMC-Somatostatin-Growth Hormone circuit. Cell Rep., 23, 1728–1741
  Löhr, H., Hess, S., Pereira, M. M. A., Reinoß, P., Leibold, S., Schenkel, C., Wunderlich, CM, Kloppen burg, P., Brüning, J. C., Hammerschmidt, M.
  
• (2018). Food intake recruits orosensory and post-ingestive dopaminergic circuits to affect eating desire in humans. Cell Metab.
  Edwin Thanarajah, S., Backes, H., Difeliceantonio, A.G., Albus, K., Cremer, A.L., Hanssen, R., Lippert, R.N., Cornely, O.A., Small, D.M., Brüning, J.C., Tittgemeyer, M.
  
• (2018). Food perception primes hepatic ER homeostasis via melanocortin-dependent control of mTOR activation. Cell 175, 1321-1335.e.1320
  Brandt, C., Nolte, H., Henschke, S., Ruud, L.E., Awazawa, M., Morgan, D.A., Gabel, P., Sprenger, H.-G., Hess, M.E., Günther, S., Langer, T., Rahmouni, K., Fenselau, H., Krüger, M., Brüning, J.C.
  
• (2018). Impact of bariatric surgery on neural food processing and cognition: an fMRI study. BMJ Open. 8, e022375
  Schulze, M., Sörös, P., Vogel, W., Münte, T.F., Müller, H.H.O., Philipsen, A.
  
• (2018). Influences of Hunger, Sa tiety and Oral Glucose on Functional Brain Connectivity: A multimethod resting-State fMRI study. Neuroscience 382, 80-92
  Al-Zubaidi, A., Heldmann, M., Mertins, A., Jauch-Chara, K., Münte, T.F.
  
• (2018). Laminar fMRI and computational theories of brain function. NeuroImage
  Stephan, K.E., Petzschner, FH., Kasper, L., Bayer, J., Wellstein, K.V., Stefanics, G., Prüssmann, K.P., Heinzle, J.
  
• (2018). P53 in AgRP neurons is required for protection against diet-induced obesity via JNK1. Nat Commu. 9, 3432
  Quiñones M., Al-Massadi O., Folgueira C., …, Sabio G. & R. Nogueiras
  
• (2018). Psychosocial stress promotes food intake and enhances the neuroenergetic level in men. Stress. 21, 538-547
  Kistenmacher, A., Goetsch, J., Ullmann, D., Wardzinski, E.K., Melchert, U.H., Jauch-Chara,K., Oltanns,K.M.
  
• (2018). Supra-additive effects of combining fat and carbohydrate on food reward. Cell Metab, 28, 33–44.e33
  Difeliceantonio, A.G., Coppin, G., Rigoux, L., Edwin Thanarajah, S., Dagher, A., Tittgemeyer, M., and Small, D.M.
  
• (2018). The LepR-mediated leptin transport across brain barriers controls food reward. Mol Metab 8, 13-22
  Di Spiezio, A., Sandin, ES., Dore, R., Muller-Fielitz, H., Storck, SE., Bernau, M., Mier, W., Oster, H., Jöhren, O., Pietrzik, CU., Lehnert, H., Schwaninger, M.
  
• (2018). Visual mismatch and predictive coding: A computational single-trial ERP study. Journal of Neuroscience 38: 4020-4030
  Stefanics, G., Heinzle, J., Horvath, A., Stephan, K.E.
  
• (2019). Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development. JCI Insight 4, Article No. e123337
  Wang, L., De Solis, A.J., Goffer, Y., Birkenbach, K.E., Engle, S.E., Tanis, R., Levenson, J.M., Li, X., Busch, R., Purohit, M., et al.
  
• (2019). Double transcranial direct current stimulation of the brain increases cerebral en ergy levels and systemic glucose tolerance in men. J. Neuroendocrinol. e12688
  Wardzinski, E.K., Friedrichsen, L., Dannenberger, S., Kistenmacher, A., Melchert, U.H., Jauch-Chara, K., and Oltmanns, K.M.
  
• (2019). Food intake recruits orosensory and postingestive dopaminergic circuits to affect eating desire in humans. Cell Metabolism 29, 695-706.e694
  Thanarajah, S.E., Backes, H., DiFeliceantonio, A.G., Albus, K., Cremer, A.L., Hanssen, R., Lippert, R.N., Cornely, O.A., Small, D.M., Brüning, J.C., et al.
  
• (2019). Intranasal oxytocin fails to acutely improve glucose metabolism in obese men. Diabetes Obes Metab 21, 424-428
  Brede, S., Fehr, S., Dalla-Man, C., Cobelli, C., Lehnert, H., Hallschmid, M., Klement, J.
  
• (2019). Mesolimbic white matter connectivity mediates the preference for sweet food. Sci. Rep. 9, 4349
  Francke, P., Tiedemann, L.J., Menz, M.M., Beck, J., Büchel, C., and Brassen, S.
  
• (2019). Sleep deprivation selectively upregulates an amygdala-hypothalamic circuit involved in food reward. J. Neurosci. 39, 888–899
  Rihm, J.S., Menz, M.M., Schultz, H., Bruder, L., Schilbach, L., Schmid, S.M., and Peters, J.
  
• (2019). The corticosteroid prednisolone increases amygdala and insula reactivity to food approach signals in healthy young men. Psychoneuroendocrinology 99, 154-165
  Serfling, G., Buades-Rotger, M., Harbeck, B., Krämer, U.M., and Brabant, G.
  
• (2019). Time-dependent assessment of stimulusevoked regional dopamine release. Nat Commun.
  Lippert, R.N., Cremer, A.L., Edwin Thanarajah, S., Korn, C., Jahans-Price, T., Burgeno, L.M., Tittgemeyer, M., Brüning, J.C., Walton, M.E., Backes, H.
  
• (2019). Timing modulates the effect of sleep loss on glucose homeostasis. J. Clin. En docrinol. Metab. 104,2801-2808
  Wilms, B., Chamorro, R., Hallschmid, M., Trost, D., Forck, N., Schultes, B., Mölle, M., Sayk, F., Lehnert, H., Schmid, S.M.