Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism
Devesh Mishra,
Jennifer E. Richard,
Ivana Maric,
Begona Porteiro,
Martin Häring,
Sander Kooijman,
Saliha Musovic,
Kim Eerola,
Lorena López-Ferreras,
Eduard Peris,
Katarzyna Grycel,
Olesya T. Shevchouk,
Peter Micallef,
Charlotta S. Olofsson,
Ingrid Wernstedt Asterholm,
Harvey J. Grill,
Ruben Nogueiras,
Karolina P. Skibicka
Affiliations
Devesh Mishra
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Jennifer E. Richard
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Ivana Maric
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Begona Porteiro
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
Martin Häring
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Sander Kooijman
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
Saliha Musovic
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Kim Eerola
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Lorena López-Ferreras
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Eduard Peris
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Katarzyna Grycel
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Olesya T. Shevchouk
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Peter Micallef
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Charlotta S. Olofsson
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Ingrid Wernstedt Asterholm
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Harvey J. Grill
Lynch Laboratory, Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA
Ruben Nogueiras
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
Karolina P. Skibicka
Department of Physiology and Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Corresponding author
Summary: Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6. : Mishra et al. demonstrate that IL-6 is produced by lPBN neurons, astrocytes, and microglia. They show that IL-6 acts in the lPBN to reduce body weight by increasing thermogenesis and reducing food intake. They also identify two pathophysiological/physiological contexts, obesity and cold exposure, that divergently affect lPBN IL-6 production. Keywords: lateral PBN, hindbrain, energy balance, cold exposure, obesity, thyroid, brown adipose tissue, diet-induced obesity, sex differences, PVN
