Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06769-y
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Funding
- Alfred Benzon Foundation
- Lundbeck Foundation
- Novo Nordisk Foundation
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [694968]
- Alexander von Humboldt Foundation
- Helmholtz Alliance ICEMED
- Initiative and Networking Fund of the Helmholtz Association
- Helmholtz initiative on Personalized Medicine iMed
- German Research Foundation [DFG-TRR152-TP23]
- HGF/ExNet project Innovative Intelligent Imaging (i3-Helmholtz)
- Helmholtz cross-program Metabolic Dysfunction
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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 (alpha 3 beta 4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR alpha 3 beta 4 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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