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; Matthias H Tschöp

doi:10.1038/s41467-018-06769-y

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 NtziachristosMichael A Cowley, Brian Finan^*, Timo D Müller, Matthias H Tschöp

^*Corresponding author for this work

The August Krogh Section for Molecular Physiology

19 Citations (Scopus)

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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.

Original language	English
Article number	4304
Journal	Nature Communications
Volume	9
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-06769-y
Publication status	Published - 2018

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Clemmensen, C., Jall, S., Kleinert, M., Quarta, C., Gruber, T., Reber, J., Sachs, S., Fischer, K., Feuchtinger, A., Karlas, A., Simonds, S. E., Grandl, G., Loher, D., Sanchez-Quant, E., Keipert, S., Jastroch, M., Hofmann, S. M., Nascimento, E. B. M., Schrauwen, P., ... Tschöp, M. H. (2018). Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes. Nature Communications, 9, Article 4304. https://doi.org/10.1038/s41467-018-06769-y

Clemmensen, C, Jall, S, Kleinert, M, Quarta, C, Gruber, T, Reber, J, Sachs, S, Fischer, K, Feuchtinger, A, Karlas, A, Simonds, SE, Grandl, G, Loher, D, Sanchez-Quant, E, Keipert, S, Jastroch, M, Hofmann, SM, Nascimento, EBM, Schrauwen, P, Ntziachristos, V, Cowley, MA, Finan, B, Müller, TD & Tschöp, MH 2018, 'Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes', Nature Communications, vol. 9, 4304. https://doi.org/10.1038/s41467-018-06769-y

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title = "Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes",

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.",

author = "Christoffer Clemmensen and Sigrid Jall and Maximilian Kleinert and Carmelo Quarta and Tim Gruber and Josefine Reber and Stephan Sachs and Katrin Fischer and Annette Feuchtinger and Angelos Karlas and Simonds, {Stephanie E} and Gerald Grandl and Daniela Loher and Eva Sanchez-Quant and Susanne Keipert and Martin Jastroch and Hofmann, {Susanna M} and Nascimento, {Emmani B M} and Patrick Schrauwen and Vasilis Ntziachristos and Cowley, {Michael A} and Brian Finan and M{\"u}ller, {Timo D} and Tsch{\"o}p, {Matthias H}",

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T1 - Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes

AU - Clemmensen, Christoffer

AU - Jall, Sigrid

AU - Kleinert, Maximilian

AU - Quarta, Carmelo

AU - Gruber, Tim

AU - Reber, Josefine

AU - Sachs, Stephan

AU - Fischer, Katrin

AU - Feuchtinger, Annette

AU - Karlas, Angelos

AU - Simonds, Stephanie E

AU - Grandl, Gerald

AU - Loher, Daniela

AU - Sanchez-Quant, Eva

AU - Keipert, Susanne

AU - Jastroch, Martin

AU - Hofmann, Susanna M

AU - Nascimento, Emmani B M

AU - Schrauwen, Patrick

AU - Ntziachristos, Vasilis

AU - Cowley, Michael A

AU - Finan, Brian

AU - Müller, Timo D

AU - Tschöp, Matthias H

N1 - Publisher Correction: Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes (vol 9, 4304, 2018) https://doi.org/10.1038/s41467-018-07479-1

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

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JO - Nature Communications

JF - Nature Communications

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

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