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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 4304 (10 23 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30353008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MC4R protein, mouse
• Melanocortins
• Pyrimidinones
• Receptor, Melanocortin, Type 4
• Receptors, Nicotinic
• TRPM Cation Channels
• TRPM8 protein, mouse
• Dimethylphenylpiperazinium Iodide
• icilin

Topics

• Adipose Tissue, Brown (drug effects, metabolism)
• Animals
• Body Weight (drug effects)
• Cold Temperature
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Diet
• Dimethylphenylpiperazinium Iodide (pharmacology, therapeutic use)
• Energy Metabolism (drug effects)
• Fatty Liver (pathology)
• Glucose Intolerance (pathology)
• Insulin Resistance
• Male
• Melanocortins (metabolism)
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (drug therapy, metabolism)
• Pyrimidinones (pharmacology, therapeutic use)
• Receptor, Melanocortin, Type 4 (metabolism)
• Receptors, Nicotinic (metabolism)
• TRPM Cation Channels (antagonists & inhibitors, metabolism)
• Thermogenesis (drug effects)