title: GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight.
abstract: The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward.
authors: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden; Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), D-85764, München-Neuherberg, Germany.
authors: Heike
authors: H
authors: Vogel
authors: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden; Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558, Nuthetal, Germany.
authors: Stefanie
authors: S
authors: Wolf
authors: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden.
authors: Cristina
authors: C
authors: Rabasa
authors: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden.
authors: Francisca
authors: F
authors: Rodriguez-Pacheco
authors: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden.
authors: Carina S
authors: CS
authors: Babaei
authors: Department Systems Physiology of Learning, Leibniz Institute for Neurobiology, D-39120, Magdeburg, Germany.
authors: Franziska
authors: F
authors: Stöber
authors: Department Systems Physiology of Learning, Leibniz Institute for Neurobiology, D-39120, Magdeburg, Germany.
authors: Jürgen
authors: J
authors: Goldschmidt
authors: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors: Richard D
authors: RD
authors: DiMarchi
authors: Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Enviromental Health (GmbH) and Technical University Munich, D-85748, Munich, Germany; German Center for Diabetes Research (DZD), D-85764, München-Neuherberg, Germany.
authors: Brian
authors: B
authors: Finan
authors: Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Enviromental Health (GmbH) and Technical University Munich, D-85748, Munich, Germany; German Center for Diabetes Research (DZD), D-85764, München-Neuherberg, Germany.
authors: Matthias H
authors: MH
authors: Tschöp
authors: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden.
authors: Suzanne L
authors: SL
authors: Dickson
authors: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, D-14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), D-85764, München-Neuherberg, Germany.
authors: Annette
authors: A
authors: Schürmann
authors: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30, Gothenburg, Sweden. Electronic address: Karolina.Skibicka@neuro.gu.se.
authors: Karolina P
authors: KP
authors: Skibicka
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology*; D001931:Brain Mapping; D002491:Central Nervous System Agents / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000008:administration & dosage / Q000378:metabolism*; D005502:Food; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000378:metabolism*; D007034:Hypothalamus, Posterior / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D012201:Reward; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D002491:Central Nervous System Agents; D004967:Estrogens; D052216:Glucagon-Like Peptide 1
keywords: Appetite; Food reward; GLP-1; Operant conditioning