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

Christoffer Clemmensen, Sigrid Jall, Maximilian Kleinert, Carmelo Quarta, Tim Gruber, Josefine Reber, Stephan Sachs, Katrin Fischer, Annette Feuchtinger, Angelos Karlas, Stephanie E. Simonds, Gerald Grandl, Daniela Loher, Eva Sanchez-Quant, Susanne Keipert, Martin Jastroch, Susanna M. Hofmann, Emmani B. M. Nascimento, Patrick Schrauwen, Vasilis Ntziachristos, Michael A. Cowley, Brian Finan (), Timo D. Müller () and Matthias H. Tschöp ()
Additional contact information
Christoffer Clemmensen: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Sigrid Jall: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Maximilian Kleinert: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Carmelo Quarta: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Tim Gruber: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Josefine Reber: German Research Center for Environmental Health (GmbH)
Stephan Sachs: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Katrin Fischer: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Annette Feuchtinger: Helmholtz Zentrum München
Angelos Karlas: German Research Center for Environmental Health (GmbH)
Stephanie E. Simonds: Monash University
Gerald Grandl: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Daniela Loher: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Eva Sanchez-Quant: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Susanne Keipert: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Martin Jastroch: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Susanna M. Hofmann: German Research Center for Environmental Health (GmbH)
Emmani B. M. Nascimento: NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center
Patrick Schrauwen: NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center
Vasilis Ntziachristos: German Research Center for Environmental Health (GmbH)
Michael A. Cowley: Monash University
Brian Finan: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Timo D. Müller: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)
Matthias H. Tschöp: Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD)

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06769-y

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