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

Christoffer Clemmensen; Sigrid Jail; 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 Jail, 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

Research output: Contribution to journal › Article › Academic › peer-review

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
Number of pages	13
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06769-y
Publication status	Published - 23 Oct 2018

Keywords

BROWN ADIPOSE-TISSUE
OPTIMAL HOUSING TEMPERATURES
CENTRAL-NERVOUS-SYSTEM
THERMAL ENVIRONMENT
ENERGY-EXPENDITURE
ACETYLCHOLINE-RECEPTORS
OPTOACOUSTIC TOMOGRAPHY
BODY-TEMPERATURE
HEALTHY-ADULTS
TRP CHANNELS
Dimethylphenylpiperazinium Iodide/pharmacology
Male
Receptor, Melanocortin, Type 4/metabolism
Fatty Liver/pathology
Body Weight/drug effects
Cold Temperature
Thermogenesis/drug effects
Mice, Inbred C57BL
Glucose Intolerance/pathology
Insulin Resistance
Melanocortins/metabolism
Pyrimidinones/pharmacology
Animals
Diabetes Mellitus, Type 2/drug therapy
Diet
TRPM Cation Channels/antagonists & inhibitors
Energy Metabolism/drug effects
Mice, Obese
Adipose Tissue, Brown/drug effects
Receptors, Nicotinic/metabolism
Obesity/drug therapy

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10.1038/s41467-018-06769-yLicence: CC BY

1 Erratum / corrigendum / retractions

Publisher Correction: Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes
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. & Ntziachristos, V. & 4 others, Cowley, M. A., Finan, B., Müller, T. D. & Tschöp , M. H., 20 Nov 2018, In: Nature Communications. 9, 1 p., 4975.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Clemmensen, C., Jail, 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(1), Article 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.",

keywords = "BROWN ADIPOSE-TISSUE, OPTIMAL HOUSING TEMPERATURES, CENTRAL-NERVOUS-SYSTEM, THERMAL ENVIRONMENT, ENERGY-EXPENDITURE, ACETYLCHOLINE-RECEPTORS, OPTOACOUSTIC TOMOGRAPHY, BODY-TEMPERATURE, HEALTHY-ADULTS, TRP CHANNELS, Dimethylphenylpiperazinium Iodide/pharmacology, Male, Receptor, Melanocortin, Type 4/metabolism, Fatty Liver/pathology, Body Weight/drug effects, Cold Temperature, Thermogenesis/drug effects, Mice, Inbred C57BL, Glucose Intolerance/pathology, Insulin Resistance, Melanocortins/metabolism, Pyrimidinones/pharmacology, Animals, Diabetes Mellitus, Type 2/drug therapy, Diet, TRPM Cation Channels/antagonists & inhibitors, Energy Metabolism/drug effects, Mice, Obese, Adipose Tissue, Brown/drug effects, Receptors, Nicotinic/metabolism, Obesity/drug therapy",

author = "Christoffer Clemmensen and Sigrid Jail 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.}",

year = "2018",

month = oct,

day = "23",

doi = "10.1038/s41467-018-06769-y",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Clemmensen, C, Jail, 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, no. 1, 4304. https://doi.org/10.1038/s41467-018-06769-y

TY - JOUR

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

AU - Clemmensen, Christoffer

AU - Jail, 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.

PY - 2018/10/23

Y1 - 2018/10/23

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.

KW - BROWN ADIPOSE-TISSUE

KW - OPTIMAL HOUSING TEMPERATURES

KW - CENTRAL-NERVOUS-SYSTEM

KW - THERMAL ENVIRONMENT

KW - ENERGY-EXPENDITURE

KW - ACETYLCHOLINE-RECEPTORS

KW - OPTOACOUSTIC TOMOGRAPHY

KW - BODY-TEMPERATURE

KW - HEALTHY-ADULTS

KW - TRP CHANNELS

KW - Dimethylphenylpiperazinium Iodide/pharmacology

KW - Male

KW - Receptor, Melanocortin, Type 4/metabolism

KW - Fatty Liver/pathology

KW - Body Weight/drug effects

KW - Cold Temperature

KW - Thermogenesis/drug effects

KW - Mice, Inbred C57BL

KW - Glucose Intolerance/pathology

KW - Insulin Resistance

KW - Melanocortins/metabolism

KW - Pyrimidinones/pharmacology

KW - Animals

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Diet

KW - TRPM Cation Channels/antagonists & inhibitors

KW - Energy Metabolism/drug effects

KW - Mice, Obese

KW - Adipose Tissue, Brown/drug effects

KW - Receptors, Nicotinic/metabolism

KW - Obesity/drug therapy

U2 - 10.1038/s41467-018-06769-y

DO - 10.1038/s41467-018-06769-y

M3 - Article

C2 - 30353008

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4304

ER -

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

Abstract

Keywords

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Research output

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

Cite this