Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.
Cell Metabolism. 2017-10-01; 26(4): 620-632.e6
DOI: 10.1016/j.cmet.2017.08.023
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Quarta C(1), Clemmensen C(1), Zhu Z(2), Yang B(2), Joseph SS(1), Lutter D(1), Yi CX(3), Graf E(4), García-Cáceres C(1), Legutko B(1), Fischer K(1), Brommage R(5),
Zizzari P(6), Franklin BS(7), Krueger M(8), Koch M(8), Vettorazzi S(9), Li P(2), Hofmann SM(10), Bakhti M(11), Bastidas-Ponce A(12), Lickert H(11), Strom TM(4),
Gailus-Durner V(5), Bechmann I(8), Perez-Tilve D(13), Tuckermann J(9), Hrabě de Angelis M(14), Sandoval D(15), Cota D(6), Latz E(7), Seeley RJ(15), Müller TD(1),
DiMarchi RD(2), Finan B(16), Tschöp MH(17).
Author information:
(1)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz
Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases,
Department of Medicine, Technische Universität München, 80333 Munich, Germany;
German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany.
(2)Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
(3)Department of Endocrinology and Metabolism, Academic Medical Center,
University of Amsterdam, 1105AZ Amsterdam, the Netherlands.
(4)Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg,
Germany.
(5)German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum
München, German Research Center for Environmental Health, 85764 Neuherberg,
Germany.
(6)INSERM, Neurocenter Magendie, Physiopathologie de la Plasticité Neuronale,
U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocenter Magendie,
Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France.
(7)Institute of Innate Immunity, University Hospital, University of Bonn, 53127
Bonn, Germany; Department of Infectious Diseases and Immunology, University of
Massachusetts Medical School, Worcester, MA 01605, USA; German Center for
Neurodegenerative Diseases, 53175 Bonn, Germany.
(8)Institute for Anatomy, University of Leipzig, 04103 Leipzig, Germany.
(9)Institute of Comparative Molecular Endocrinology, University of Ulm, 89081
Ulm, Germany.
(10)German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany; Institute for Diabetes and
Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German
Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany;
Medizinische Klinik und Poliklinik IV, Klinikum der LMU, 80336 Munich, Germany.
(11)German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany; Institute for Diabetes and
Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German
Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany;
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg,
Germany; Technische Universität München, 81675 Munich, Germany.
(12)German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany; Institute for Diabetes and
Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German
Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany;
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg,
Germany.
(13)Department of Internal Medicine, University of Cincinnati College of
Medicine, Cincinnati, OH 45267, USA.
(14)German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany; German Mouse Clinic,
Institute of Experimental Genetics, Helmholtz Zentrum München, German Research
Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Experimental
Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität
München, Munich, Germany.
(15)Department of Surgery, University of Michigan, Ann Arbor, MI 48109-2800, USA.
(16)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz
Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases,
Department of Medicine, Technische Universität München, 80333 Munich, Germany;
German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany. Electronic address:
.
(17)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz
Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases,
Department of Medicine, Technische Universität München, 80333 Munich, Germany;
German Center for Diabetes Research (DZD), Helmholtz Zentrum München,
Ingolstädter Landstraße, 85764 Neuherberg, Germany. Electronic address:
.
Chronic inflammation has been proposed to contribute to the pathogenesis of
diet-induced obesity. However, scarce therapeutic options are available to treat
obesity and the associated immunometabolic complications. Glucocorticoids are
routinely employed for the management of inflammatory diseases, but their
pleiotropic nature leads to detrimental metabolic side effects. We developed
a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1
selectively delivers dexamethasone to GLP-1 receptor-expressing cells.
GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the
hypothalamic control of feeding and by increasing energy expenditure. This
strategy reverses hypothalamic and systemic inflammation while improving glucose
tolerance and insulin sensitivity. The selective preference for GLP-1 receptor
bypasses deleterious effects of dexamethasone on glucose handling, bone
integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed
glucocorticoid pharmacology represents a safe and efficacious therapy option for
diet-induced immunometabolic derangements and the resulting obesity.