TY - JOUR

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.

UR - https://www.nature.com/articles/s41467-018-07479-1

U2 - 10.1038/s41467-018-06769-y

DO - 10.1038/s41467-018-06769-y

M3 - Journal article

C2 - 30353008

AN - SCOPUS:85055463198

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4304

ER -