Center for Molecular Medicine Cologne

Brüning, Jens C - C 05

Role of prepronociceptin (PNOC)-expressing neurons in the development of obesity


Obesity and obesity-associated type 2 diabetes mellitus are on constant epidemiological rise and only limited therapeutic options exist. Nevertheless, the neuronal mechanisms underlying deregulated energy homeostasis during consumption of calorie dense food are not yet defined.

Unravelling novel neurocircuits in control of feeding, defining their deregulation in obesity development and identifying drugable targets on these circuits to modulate their activity pharmacologically represents a critical prerequisite to develop novel therapeutic approaches for these diseases.

Hypothalamic neurocircuits are key regulators of energy homeostasis and systemic glucose metabolism, and their deregulation upon consumption of highly palatable, calorie-rich diets represents a central mechanism in the development of obesity and type 2 diabetes mellitus.

Particularly, the inhibition of food-intake suppressing proopiomelanocortin (POMC)-expressing neurons has been demonstrated to contribute to this effect, and the mechanisms of obesity-induced POMC neuron inhibition include both cell autonomous impairments as well as increased inhibitory synaptic contacts.

We have identified a previously unrecognized population of GABAergic, inhibitory prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC), which are readily activated upon high fat feeding of mice, and which provide inhibitory synaptic input to POMC neurons.

Therefore, these neurons may be central to the diet-induced synaptic inhibition of critical feeding-regulatory POMC neurons during obesity development. In the current proposal, we aim at 1. characterizing the cell-intrinsic properties of hypothalamic PNOC neurons, 2. defining their neuronal network structure, 3. unraveling their regulation in vivo.

Collectively the project addresses a question of utmost clinical importance with the ultimate aim to define novel mechanisms for pharmacological intervention with prevalent metabolic disorders, for which currently only limited therapies exist.

Our Aims

  1. Molecularly define PNOC Neurons
  2. Identify their neuronal network structure
  3. Define their physiologicaly and pathophysiologically relevant regulatory mechanisms
  • Hoyer-Allo KJR, Spath MR, Brodesser S, Zhu Y, Binz-Lotter J, Hohne M, Broenneke H, Bohl K, Johnsen M, Kubacki T, Kiefer K, Seufert L, Koehler FC, Grundmann F, Hackl MJ, Schermer B, Bruning J, Benzing T, Burst V, and Muller RU (2022). Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury. Kidney Int. doi:10.1016/j.kint.2022.04.033.
  • Matsushita M, Awazawa M, Kobayashi N, Ikushima YM, Soeda K, Tamura-Nakano M, Muratani M, Kobayashi K, Bluher M, Bruning JC, and Ueki K (2022). An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance. Cell Chem Biol29, 680-689 e686. doi:10.1016/j.chembiol.2021.12.008.
  • Jais A, and Bruning JC (2022). Arcuate Nucleus-Dependent Regulation of Metabolism-Pathways to Obesity and Diabetes Mellitus. Endocr Rev43, 314-328. doi:10.1210/endrev/bnab025.
  • Aravamudhan S, Turk C, Bock T, Keufgens L, Nolte H, Lang F, Krishnan RK, Konig T, Hammerschmidt P, Schindler N, Brodesser S, Rozsivalova DH, Rugarli E,Trifunovic A, Bruning J, Langer T, Braun T, and Kruger M (2021). Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein. J Mol Cell Cardiol154, 41-59. doi:10.1016/j.yjmcc.2021.01.010.
                            • 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, and Bruning JC (2021). Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nat Neurosci24, 913-929. doi:10.1038/s41593-021-00854-0.
                                    • Borgmann D, Ciglieri E, Biglari N, Brandt C, Cremer AL, Backes H, Tittgemeyer M, Wunderlich FT, Bruning JC, and Fenselau H (2021). Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism. Cell Metab33, 1466-1482 e1467. doi:10.1016/j.cmet.2021.05.002.
                                                                            • Dodd GT, Kim SJ, Mequinion M, Xirouchaki CE, Bruning JC, Andrews ZB, and Tiganis T (2021). Insulin signaling in AgRP neurons regulates meal size to limit glucose excursions and insulin resistance. Sci Adv7. doi:10.1126/sciadv.abf4100.
                                                                            • Hoyer-Allo KJR, Spath MR, Hanssen R, Johnsen M, Brodesser S, Kaufmann K, Kiefer K, Koehler FC, Gobel H, Kubacki T, Grundmann F, Schermer B, Bruning J, Benzing T, Burst V, and Muller RU (2021). Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury. Int J Mol Sci22. doi:10.3390/ijms22115485.
                                                                                                                                                                                                        • Kohlhaas V, Blakemore SJ, Al-Maarri M, Nickel N, Pal M, Roth A, Hovelmeyer N, Schafer SC, Knittel G, Lohneis P, Nikolic M, Wiederstein JL, Franitza M, Georgomonolis T, Reinart N, Herling M, Herling C, Hartmann EM, Rosenwald A, Klapper W, Buttner R, Moia R, Rossi D, Boldorini R, Gaidano G, Frenzel LP, Reinhardt HC, Bruning JC, Hallek M, Kruger M, Peifer M, Pallasch CP, and Wunderlich FT (2021). Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. Blood137, 646-660. doi:10.1182/blood.2020005734.
                                                                                                                                                                                                                                                • Matsushita M, Awazawa M, Kobayashi N, Ikushima YM, Soeda K, Tamura-Nakano M, Muratani M, Kobayashi K, Bluher M, Bruning JC, and Ueki K (2021). An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance. Cell Chem Biol. doi:10.1016/j.chembiol.2021.12.008.
                                                                                                                                                                                                                                                                                                                                                                                                                                    • Welcker D, Stein C, Feitosa NM, Armistead J, Zhang JL, Lutke S, Kleinridders A, Bruning JC, Eming SA, Sengle G, Niehoff A, Bloch W, and Hammerschmidt M (2021). Hemicentin-1 is an essential extracellular matrix component of the dermal-epidermal and myotendinous junctions. Sci Rep11, 17926. doi:10.1038/s41598-021-96824-4.
                                                                                                                                                                                                                                                                                                                                                                                                                                      • Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nuchel J, Popovic M, MacVicar T, Langer T, Schultze JL, Gerbaulet A, Roers A, Pearce EJ, Bruning JC, Trifunovic A, and Eming SA (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab33, 2398-2414 e2399. doi:10.1016/j.cmet.2021.10.004.
                                                                                                                                                                                                                                                                                                                                                                                                                                                • Xiao X, Yeghiazaryan G, Hess S, Klemm P, Sieben A, Kleinridders A, Morgan DA, Wunderlich FT, Rahmouni K, Kong D, Scammell TE, Lowell BB, Kloppenburg P, Bruning JC, and Hausen AC (2021). Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity. Nat Commun12, 5249. doi:10.1038/s41467-021-25380-2.
                                                                                                                                                                                                                                                                                                                                                                                                                                                • Jais A, and Bruning JC (2021). Arcuate nucleus-dependent regulation of metabolism - pathways to obesity and diabetes mellitus. Endocr Rev. doi:10.1210/endrev/bnab025.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Quarta C, Claret M, Zeltser LM, Williams KW, Yeo GSH, Tschop MH, Diano S, Bruning JC, and Cota D (2021). POMC neuronal heterogeneity in energy balance and beyond: an integrated view. Nat Metab3, 299-308. doi:10.1038/s42255-021-00345-3.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Ding X, Willenborg S, Bloch W, Wickstrom SA, Wagle P, Brodesser S, Roers A, Jais A, Bruning JC, Hall MN, Ruegg MA, and Eming SA (2020). Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. J Allergy Clin Immunol 145, 283-300 e8.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • DiToro D, Harbour SN, Bando JK, Benavides G, Witte S, Laufer VA, Moseley C, Singer JR, Frey B, Turner H, Bruning J, Darley-Usmar V, Gao M, Conover C, Hatton RD, Frank S, Colonna M, and Weaver CT (2020). Insulin-Like Growth Factors Are Key Regulators of T Helper 17 Regulatory T Cell Balance in Autoimmunity. Immunity 52, 650-67 e10.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Engstrom Ruud L, Pereira MMA, de Solis AJ, Fenselau H, and Bruning JC (2020). NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons. Nat Commun 11, 442.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Bruning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschop MH, and Muller TD (2020). The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. Nat Commun 11, 2306.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Jais A, Paeger L, Sotelo-Hitschfeld T, Bremser S, Prinzensteiner M, Klemm P, Mykytiuk V, Widdershooven PJM, Vesting AJ, Grzelka K, Minere M, Cremer AL, Xu J, Korotkova T, Lowell BB, Zeilhofer HU, Backes H, Fenselau H, Wunderlich FT, Kloppenburg P, and Bruning JC (2020). PNOC(ARC) Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding. Neuron 10.1016/j.neuron.2020.03.022.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Jiang H, Gallet S, Klemm P, Scholl P, Folz-Donahue K, Altmuller J, Alber J, Heilinger C, Kukat C, Loyens A, Muller-Fielitz H, Sundaram S, Schwaninger M, Prevot V, and Bruning JC (2020). MCH Neurons Regulate Permeability of the Median Eminence Barrier. Neuron 10.1016/j.neuron.2020.04.020.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Ruud LE, Pereira MMA, de Solis AJ, Fenselau H, and Bruning JC (2020). NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons. Nat Commun 11.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Timper K, Del Rio-Martin A, Cremer AL, Bremser S, Alber J, Giavalisco P, Varela L, Heilinger C, Nolte H, Trifunovic A, Horvath TL, Kloppenburg P, Backes H, and Bruning JC (2020). GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function. Cell Metab 31, 1189-205 e13.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                • Turpin-Nolan SM, and Bruning JC (2020). The role of ceramides in metabolic disorders: when size and localization matters. Nat Rev Endocrinol 16, 224-33.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                Prof. Dr. Jens C Brüning CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                                                                                                                                Prof. Dr. Jens C Brüning

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Center for Endocrinology, Diabetes and Preventive Medicine

                                                                                                                                                                                                                                                                                                                                                                                                                                                                CMMC - PI - C 06 

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Executive Board Member

                                                                                                                                                                                                                                                                                                                                                                                                                                                                +49 221 470 2467

                                                                                                                                                                                                                                                                                                                                                                                                                                                                +49 221 470 5185

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Center for Endocrinology, Diabetes and Preventive Medicine

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Kerpener Str. 62

                                                                                                                                                                                                                                                                                                                                                                                                                                                                50937 Cologne


                                                                                                                                                                                                                                                                                                                                                                                                                                                                CMMC Profile Page

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Curriculum Vitae (CV)

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Publications - Jens C Brüning

                                                                                                                                                                                                                                                                                                                                                                                                                                                                Link to PubMed