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 journalArticleAcademicpeer-review

28 Citations (Web of Science)

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 languageEnglish
Article number4304
Number of pages13
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 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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