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The Glucose-Dependent Insulinotropic Polypeptide (GIP) Regulates Body Weight and Food Intake Via CNS-GIPR Signaling

33 Pages Posted: 5 Aug 2020 Publication Status: Published

See all articles by Qian Zhang

Qian Zhang

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Challa Tenagne Delessa

Institute of Food, Nutrition and Health, Department of Health Sciences and Technology (D-HEST), ETH Zürich

Robert Augustin

Cardiometabolic Diseases Research Department, Boehringer Ingelheim Pharma GmbH

Mostafa Bakhti

German Center for Diabetes Research (DZD)

Gustav Colldén

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Daniel J. Drucker

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto

Annette Feuchtinger

Helmholtz Association of German Research Centres - Research Unit Analytical Pathology

Cristina Garcia Caceres

German Research Center for Environmental Health - Institute for Diabetes and Obesity

Gerald Grandl

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Alexandra Harger

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Susanna Hofmann

German Center for Diabetes Research (DZD)

Cassie Lynn Hollemann

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Maximilian Kleinert

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Patrick J. Knerr

Novo Nordisk Research Center Indianapolis

Konxhe Kulaj

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Beata Legutko

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Heiko Lickert

German Center for Diabetes Research (DZD)

Xue Liu

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Gerd Luippold

Cardiometabolic Diseases Research Department, Boehringer Ingelheim Pharma GmbH

Emilija Malogajski

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Marta Tarquis Medina

German Center for Diabetes Research (DZD)

Stephanie Mowery

Novo Nordisk Research Center Indianapolis

Andreas Parzefall

Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg

Diego Perez-Tilve

Department of Pharmacology and Systems Physiology, University of Cincinnati-College of Medicine

Ciro Salinno

German Center for Diabetes Research (DZD)

Laura Sehrer

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Richard D. DiMarchi

Indiana University - Department of Chemistry; Indiana University; Novo Nordisk - Global Research; Indiana University

Matthias H. Tschöp

German Research Center for Environmental Health - Institute for Diabetes and Obesity

Kerstin Stemmer

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Brian Finan

Novo Nordisk Research Center Indianapolis

Christian Wolfrum

ETH Zürich - Institute of Food, Nutrition and Health

Timo D. Müller

German Research Center for Environmental Health - Institute for Diabetes and Obesity

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Abstract

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. We show that HFD-fed CNS-Gipr ko mice and humanized (h)GIPR knock-in mice with CNS-hGIPR deletion show improved body weight and glycemia, but these metabolic improvements vanish upon adult-onset Gipr deletion. In DIO mice, acute central administration of acyl-GIP increases cFos neuronal activity in the arcuate, dorsomedial, paraventricular and lateral hypothalamus and leads to improved body weight, food intake, and glycemia. Chronic administration of acyl-GIP improves body weight and food intake in wildtype mice, but shows blunted/absent efficacy in CNS-Gipr ko mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 was extinguished in CNS-Gipr ko mice. Our data establish a key role of CNS Gipr for control of energy metabolism.

Keywords: GIP, food intake, diet-induced obesity, type-2 diabetes, CNS

Suggested Citation

Zhang, Qian and Delessa, Challa Tenagne and Augustin, Robert and Bakhti, Mostafa and Colldén, Gustav and Drucker, Daniel J. and Feuchtinger, Annette and Caceres, Cristina Garcia and Grandl, Gerald and Harger, Alexandra and Hofmann, Susanna and Hollemann, Cassie Lynn and Kleinert, Maximilian and Knerr, Patrick J. and Kulaj, Konxhe and Legutko, Beata and Lickert, Heiko and Liu, Xue and Luippold, Gerd and Malogajski, Emilija and Medina, Marta Tarquis and Mowery, Stephanie and Parzefall, Andreas and Perez-Tilve, Diego and Salinno, Ciro and Sehrer, Laura and DiMarchi, Richard D. and Tschöp, Matthias H. and Stemmer, Kerstin and Finan, Brian and Wolfrum, Christian and Müller, Timo D., The Glucose-Dependent Insulinotropic Polypeptide (GIP) Regulates Body Weight and Food Intake Via CNS-GIPR Signaling. Available at SSRN: https://ssrn.com/abstract=3667144 or http://dx.doi.org/10.2139/ssrn.3667144
This version of the paper has not been formally peer reviewed.

Qian Zhang

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Challa Tenagne Delessa

Institute of Food, Nutrition and Health, Department of Health Sciences and Technology (D-HEST), ETH Zürich ( email )

Robert Augustin

Cardiometabolic Diseases Research Department, Boehringer Ingelheim Pharma GmbH ( email )

Mostafa Bakhti

German Center for Diabetes Research (DZD) ( email )

Gustav Colldén

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Daniel J. Drucker

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto ( email )

Annette Feuchtinger

Helmholtz Association of German Research Centres - Research Unit Analytical Pathology ( email )

Cristina Garcia Caceres

German Research Center for Environmental Health - Institute for Diabetes and Obesity ( email )

Gerald Grandl

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Alexandra Harger

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Susanna Hofmann

German Center for Diabetes Research (DZD) ( email )

Cassie Lynn Hollemann

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Maximilian Kleinert

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Patrick J. Knerr

Novo Nordisk Research Center Indianapolis ( email )

Konxhe Kulaj

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Beata Legutko

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Heiko Lickert

German Center for Diabetes Research (DZD) ( email )

Xue Liu

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München

Gerd Luippold

Cardiometabolic Diseases Research Department, Boehringer Ingelheim Pharma GmbH ( email )

Emilija Malogajski

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Marta Tarquis Medina

German Center for Diabetes Research (DZD) ( email )

Stephanie Mowery

Novo Nordisk Research Center Indianapolis ( email )

Andreas Parzefall

Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg ( email )

Diego Perez-Tilve

Department of Pharmacology and Systems Physiology, University of Cincinnati-College of Medicine ( email )

Ciro Salinno

German Center for Diabetes Research (DZD) ( email )

Laura Sehrer

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Richard D. DiMarchi

Indiana University - Department of Chemistry ( email )

Indiana University ( email )

107 S Indiana Ave
100 South Woodlawn
Bloomington, IN 47405
United States

Novo Nordisk - Global Research ( email )

Måløv
Denmark

Indiana University ( email )

107 S Indiana Ave
100 South Woodlawn
Bloomington, IN 47405
United States

Matthias H. Tschöp

German Research Center for Environmental Health - Institute for Diabetes and Obesity ( email )

Kerstin Stemmer

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München ( email )

Brian Finan

Novo Nordisk Research Center Indianapolis ( email )

Christian Wolfrum

ETH Zürich - Institute of Food, Nutrition and Health ( email )

Schorenstr. 16
Schwerzenbach, 8603
Switzerland

Timo D. Müller (Contact Author)

German Research Center for Environmental Health - Institute for Diabetes and Obesity ( email )

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