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Nat Commun. 2018 Oct 23;9(1):4304. doi: 10.1038/s41467-018-06769-y.

Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes.

Author information

1
Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany.
2
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
4
Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
5
Institute of Biological and Medical Imaging, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
6
Chair for Biological Imaging, Technical University of Munich, Munich, Germany.
7
Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
8
Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
9
Department of Physiology, and Biomedicine Discovery Institute, Monash University, Clayton, Australia.
10
German Center for Diabetes Research (DZD), Neuherberg, Germany.
11
Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilian Universität (LMU), Munich, Germany.
12
Department of Human Biology and Human Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands.
13
Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany. brian.finan@helmholtz-muenchen.de.
14
Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany. timo.mueller@helmholtz-muenchen.de.
15
Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany. matthias.tschoep@helmholtz-muenchen.de.
16
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany. matthias.tschoep@helmholtz-muenchen.de.

Abstract

Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

PMID:
30353008
PMCID:
PMC6199300
DOI:
10.1038/s41467-018-06769-y
[Indexed for MEDLINE]
Free PMC Article

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