Brüning, Jens C - C 03

Identification and characterization of the specific subpopulation of prepronociceptin (PNOC)-expressing neurons responsible for the development of diet-induced obesity

Prof. Dr. Jens C Brüning
Prof. Dr. Jens C Brüning

Policlinic for Endocrinology, Diabetes and Preventive Medicine

CMMC - PI - C 03
Executive Board Member

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Policlinic for Endocrinology, Diabetes and Preventive Medicine

Kerpener Str. 62

50937 Cologne

Introduction

There is an unmet global medical need to develop novel therapeutic approaches for the treatment of obesity and obesity-associated insulin resistance and type 2-diabetes mellitus.

During the last funding period of the CMMC we have identified a novel neuronal cell type, located in the arcuate nucleus of the hypothalamus (ARC), characterized by the expression of the neuropeptide Prepronociceptin (PNOC). These cells are readily activated upon consumption of a highly palatable, calory-dense food, their optogenetic activation promotes food intake in part via inhibition of food intake-suppressing, anorexigenic pro-opiomelanocortin (POMC)-expressing neurons, and their ablation protects from the development of high-fat diet (HFD)-induced obesity in mice.

Collectively, PNOCARC neurons represent a novel neuronal subclass of critical importance for the development of obesity, which is potentially amendable for novel therapeutic interventions. Further analysis of these neurons via single nuclei sequencing of hypothalamic neurons as well as multiscope RNA in situ hybridization revealed a considerable degree of heterogeneity within this cell population. Therefore, the aim of the current proposal is to define the critical subset of PNOCARC neurons, which is responsible for obesity development.

Clinical Relevance

PNOCARC neurons represent an attractive novel target for the treatment of obesity and obesity-associated co-morbidities such as type 2-diabetes mellitus, non-alcoholic steatohepatitis (NASH) as well as cardiovascular complications. Defining the specific subset of PNOCARC neurons responsible for obesity-induced weight gain carries a potential to identify novel druggable targets for specific inhibition of PNOCARC neurons in obesity.

Approach

  • Identify the specific subpopulation of PNOCARC neurons responsible for the development of diet-induced obesity.
  • Define the transcriptional profile of these specific PNOCARC neurons responsible for the development of obesity and associated metabolic diseases.

Publication Record on PubMed - Jens Brüning

2024 (up to June)
  • De Solis AJ, Del Rio-Martin A, Radermacher J, Chen W, Steuernagel L, Bauder CA, Eggersmann FR, Morgan DA, Cremer AL, Sue M, Germer M, Kukat C, Vollmar S, Backes H, Rahmouni K, Kloppenburg P, and Bruning JC (2024). Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism. Nat Metab6, 473-493. doi:10.1038/s42255-024-00987-z.
     
  • Henschke S, Nolte H, Magoley J, Kleele T, Brandt C, Hausen AC, Wunderlich CM, Bauder CA, Aschauer P, Manley S, Langer T, Wunderlich FT, and Bruning JC (2024). Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver. Science384, 438-446. doi:10.1126/science.adk1005.
     
  • Leon S, Simon V, Lee TH, Steuernagel L, Clark S, Biglari N, Leste-Lasserre T, Dupuy N, Cannich A, Bellocchio L, Zizzari P, Allard C, Gonzales D, Le Feuvre Y, Lhuillier E, Brochard A, Nicolas JC, Teillon J, Nikolski M, Marsicano G, Fioramonti X, Bruning JC, Cota D, and Quarta C (2024). Single cell tracing of Pomc neurons reveals recruitment of 'Ghost' subtypes with atypical identity in a mouse model of obesity. Nat Commun15, 3443. doi:10.1038/s41467-024-47877-2.
     
  • Vossen C, Schmidt P, Wunderlich CM, Mittenbuhler MJ, Tapken C, Wienand P, Mirabella PN, Cabot L, Schumacher AL, Folz-Donahue K, Kukat C, Voigt I, Bruning JC, Fenselau H, and Wunderlich FT (2024). An Approach to Intersectionally Target Mature Enteroendocrine Cells in the Small Intestine of Mice. Cells13. doi:10.3390/cells13010102.
     
  • Zhou X, Stine C, Prada PO, Fusca D, Assoumou K, Dernic J, Bhat MA, Achanta AS, Johnson JC, Pasqualini AL, Jadhav S, Bauder CA, Steuernagel L, Ravotto L, Benke D, Weber B, Suko A, Palmiter RD, Stoeber M, Kloppenburg P, Bruning JC, Bruchas MR, and Patriarchi T (2024). Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release. bioRxiv. doi:10.1101/2023.05.26.542102.
2023
  • Bruning JC, and Fenselau H (2023). Integrative neurocircuits that control metabolism and food intake. Science 381, eabl7398. doi:10.1126/science.abl7398.
     
  • 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, and Bruning 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.
     
  • Griess K, Rieck M, Muller N, Karsai G, Hartwig S, Pelligra A, Hardt R, Schlegel C, Kuboth J, Uhlemeyer C, Trenkamp S, Jeruschke K, Weiss J, Peifer-Weiss L, Xu W, Cames S, Yi X, Cnop M, Beller M, Stark H, Kondadi AK, Reichert AS, Markgraf D, Wammers M, Haussinger D, Kuss O, Lehr S, Eizirik D, Lickert H, Lammert E, Roden M, Winter D, Al-Hasani H, Hoglinger D, Hornemann T, Bruning JC, and Belgardt BF (2023). Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nat Cell Biol 25, 20-29. doi:10.1038/s41556-022-01027-2.
     
  • Hammerschmidt P, Steculorum SM, Bandet CL, Del Rio-Martin 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, and Bruning JC (2023). CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nat Commun 14, 7824. doi:10.1038/s41467-023-42595-7.
     
  • Klapproth H, Huerta Arana M, and Fabri M (2023). Macrophage Biology in Human Granulomatous Skin Inflammation. Int J Mol Sci 24. doi:10.3390/ijms24054624.
     
  • Klapproth H, Klapproth L, Ruegamer T, Uhl F, Jantsch J, and Fabri M (2023). [Bacterial infections of the skin in the context of climate change and migration]. Dermatologie (Heidelb) 74, 851-857. doi:10.1007/s00105-023-05231-5.
     
  • Zhou X, Stine C, Prada PO, Fusca D, Assoumou K, Dernic J, Bhat MA, Achanta AS, Johnson JC, Jadhav S, Bauder CA, Steuernagel L, Ravotto L, Benke D, Weber B, Stoeber M, Kloppenburg P, Bruning JC, Bruchas MR, and Patriarchi T (2023). Development of a genetically-encoded sensor for probing endogenous nociceptin opioid peptide release. bioRxiv. doi:10.1101/2023.05.26.542102.

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