CMMC: Jens C Brüning

Introduction

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

Molecularly define PNOC Neurons
Identify their neuronal network structure
Define their physiologicaly and pathophysiologically relevant regulatory mechanisms

Publications 2020

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.