GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia
Tamara Sotelo-Hitschfeld,
Marielle Minère,
Paul Klemm,
Diba Borgmann,
Daria Wnuk-Lipinski,
Alexander Jais,
Xianglian Jia,
Svenja Corneliussen,
Peter Kloppenburg,
Henning Fenselau,
Jens Claus Brüning
Affiliations
Tamara Sotelo-Hitschfeld
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Marielle Minère
Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Synaptic Transmission in Energy Homeostasis Research Group, Max Planck Institute for Metabolism Research, Cologne, Germany
Paul Klemm
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Diba Borgmann
Synaptic Transmission in Energy Homeostasis Research Group, Max Planck Institute for Metabolism Research, Cologne, Germany
Daria Wnuk-Lipinski
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Alexander Jais
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
Xianglian Jia
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Svenja Corneliussen
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Institute of Zoology, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany
Peter Kloppenburg
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Institute of Zoology, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany
Henning Fenselau
Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Synaptic Transmission in Energy Homeostasis Research Group, Max Planck Institute for Metabolism Research, Cologne, Germany; Corresponding author
Jens Claus Brüning
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Corresponding author
Summary: Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOCARC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOCARC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOCARC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual PNOCARC neuron activity via Ca2+ imaging, we find a subpopulation of PNOCARC neurons that is inhibited upon gastrointestinal calorie sensing and disinhibited upon HFD feeding. Combining retrograde rabies tracing and circuit mapping, we find that PNOC neurons from the bed nucleus of the stria terminalis (PNOCBNST) provide inhibitory input to PNOCARC neurons, and this inhibitory input is blunted upon HFD feeding. This work sheds light on how an increase in caloric content of the diet can rewire a neuronal circuit, paving the way to overconsumption and obesity development.
