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Mol Metab. 2017 Mar 1;6(5):440-446. doi: 10.1016/j.molmet.2017.02.002. eCollection 2017 May.

Monomeric GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice.

Author information

1
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
2
Institute for Diabetes and Obesity, 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 München, Germany.
3
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
4
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
5
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
6
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address: timo.mueller@helmholtz-muenchen.de.
7
German Center for Diabetes Research (DZD), 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 München, Germany. Electronic address: susanna.hofmann@helmholtz-muenchen.de.

Abstract

OBJECTIVE:

Obesity is a major health threat that affects men and women equally. Despite this fact, weight-loss potential of pharmacotherapies is typically first evaluated in male mouse models of diet-induced obesity (DIO). To address this disparity we herein determined whether a monomeric peptide with agonism at the receptors for glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon is equally efficient in correcting DIO, dyslipidemia, and glucose metabolism in DIO female mice as it has been previously established for DIO male mice.

METHODS:

Female C57BL/6J mice and a cohort of fatmass-matched C57BL/6J male mice were treated for 27 days via subcutaneous injections with either the GLP-1/GIP/glucagon triagonist or PBS. A second cohort of C57BL/6J male mice was included to match the females in the duration of the high-fat, high-sugar diet (HFD) exposure.

RESULTS:

Our results show that GLP-1/GIP/glucagon triple agonism inhibits food intake and decreases body weight and body fat mass with comparable potency in male and female mice that have been matched for body fat mass. Treatment improved dyslipidemia in both sexes and reversed diet-induced steatohepatitis to a larger extent in female mice compared to male mice.

CONCLUSIONS:

We herein show that a recently developed unimolecular peptide triagonist is equally efficient in both sexes, suggesting that this polypharmaceutical strategy might be a relevant alternative to bariatric surgery for the treatment of obesity and related metabolic disorders.

KEYWORDS:

Diabetes; Dyslipidemia; Glucose homeostasis; Obesity; Pharmacotherapy; Sex differences

PMID:
28462078
PMCID:
PMC5404097
DOI:
10.1016/j.molmet.2017.02.002
[Indexed for MEDLINE]
Free PMC Article

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