IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling
Katharina Timper,
Jesse Lee Denson,
Sophie Marie Steculorum,
Christian Heilinger,
Linda Engström-Ruud,
Claudia Maria Wunderlich,
Stefan Rose-John,
F. Thomas Wunderlich,
Jens Claus Brüning
Affiliations
Katharina Timper
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany
Jesse Lee Denson
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany
Sophie Marie Steculorum
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany
Christian Heilinger
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany
Linda Engström-Ruud
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany
Claudia Maria Wunderlich
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany
Stefan Rose-John
Biochemical Institute, University of Kiel, 24098 Kiel, Germany
F. Thomas Wunderlich
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany; Corresponding author
Jens Claus Brüning
Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Str. 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Str. 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-Str. 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Corresponding author
Summary: Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance. : Timper et al. find that central IL-6 improves energy and glucose homeostasis via IL-6 trans-signaling. IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance. Keywords: interleukin-6, CNS, obesity, interleukin-6 trans-signaling, energy homeostasis, glucose homeostasis
