title: Chronic l-menthol-induced browning of white adipose tissue hypothesis: A putative therapeutic regime for combating obesity and improving metabolic health.
abstract: BACKGROUND
  Obesity constitutes a serious global health concern reaching pandemic prevalence rates. The existence of functional brown adipose tissue (BAT) in adult humans has provoked intense research interest in the role of this metabolically active tissue in whole-body energy balance and body weight regulation. A number of environmental, physiological, pathological, and pharmacological stimuli have been proposed to induce BAT-mediated thermogenesis and functional thermogenic BAT-like activity in white adipose tissue (WAT), opening new avenues for therapeutic strategies based on enhancing the number of beige adipocytes in WAT.
  
  
  OBJECTIVE
  Recent evidence support a role of l-menthol cooling, mediated by TRPM8 receptor, on UCP1-dependent thermogenesis and BAT-like activity in classical WAT depots along with the recruitment of BAT at specific anatomical sites. l-Menthol-induced BAT thermogenesis has been suggested to occur by a β-adrenergic-independent mechanism, avoiding potential side-effects due to extensive β-adrenergic stimulation mediated by available beta receptor agonists. l-Menthol has been also linked to the activation of the cold-gated ion channel TRPA1. However, its role in l-menthol-induced UCP1-dependent thermogenic activity in BAT and WAT remains undetermined. White adipose tissue plasticity has important clinical implications for obesity prevention and/or treatment because higher levels of UCP1-dependent thermogenesis can lead to enhanced energy expenditure at a considerable extent. We hypothesize that chronic dietary l-menthol treatment could induce TRPM8- and TRPA1-dependent WAT adaptations, resembling BAT-like activity, and overall improve whole-body metabolic health in obese and overweight individuals.
  
  
  CONCLUSIONS
  The putative impact of chronic l-menthol dietary treatment on the stimulation of BAT-like activity in classical WAT depots in humans remains unknown. A detailed experimental design has been proposed to investigate the hypothesized l-menthol-induced browning of WAT. If our hypothesis was to be confirmed, TRPM8/TRPA1-induced metabolic adaptations of WAT to BAT-like activity could provide a promising novel therapeutic approach for increasing energy expenditure, regulating body weight, and preventing obesity and its related co-morbidities in humans.
authors.affiliation: Institute of Research and Technology Thessaly, Centre for Research and Technology Hellas, Trikala, Greece; FAME Laboratory, Department of Exercise Sciences, University of Thessaly, Trikala, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Sakellariou
authors.affiliation: FAME Laboratory, Department of Exercise Sciences, University of Thessaly, Trikala, Greece; Department of Human Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Angelica
authors.initials: A
authors.lastname: Valente
authors.affiliation: FAME Laboratory, Department of Exercise Sciences, University of Thessaly, Trikala, Greece; Department of Exercise Science, Chatham University, Pittsburgh, PA, USA.
authors.forename: Andres E
authors.initials: AE
authors.lastname: Carrillo
authors.affiliation: Faculty of Education, Health and Wellbeing, Wolverhampton University, Walsall Campus, UK.
authors.forename: George S
authors.initials: GS
authors.lastname: Metsios
authors.affiliation: Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, Grodno, Belarus.
authors.forename: Liliya
authors.initials: L
authors.lastname: Nadolnik
authors.affiliation: FAME Laboratory, Department of Exercise Sciences, University of Thessaly, Trikala, Greece.
authors.forename: Athanasios Z
authors.initials: AZ
authors.lastname: Jamurtas
authors.affiliation: FAME Laboratory, Department of Exercise Sciences, University of Thessaly, Trikala, Greece; Faculty of Education, Health and Wellbeing, Wolverhampton University, Walsall Campus, UK.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Koutedakis
authors.affiliation: Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Curitiba, Brazil.
authors.forename: Cesar
authors.initials: C
authors.lastname: Boguszewski
authors.affiliation: Department of Chemistry, Federal University of Mato Grosso, Cuiabá, Mato Grosso, Brazil.
authors.forename: Cláudia Marlise Balbinotti
authors.initials: CM
authors.lastname: Andrade
authors.affiliation: Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Svensson
authors.affiliation: Department of Chemistry, Federal University of Mato Grosso, Cuiabá, Mato Grosso, Brazil.
authors.forename: Nair Honda
authors.initials: NH
authors.lastname: Kawashita
authors.affiliation: Institute of Research and Technology Thessaly, Centre for Research and Technology Hellas, Trikala, Greece; FAME Laboratory, Department of Exercise Sciences, University of Thessaly, Trikala, Greece. Electronic address: andreasflouris@gmail.com.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Flouris
mesh_terms: D002001:Adipose Tissue, Brown / Q000502:physiology*; D052436:Adipose Tissue, White / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D015897:Comorbidity; D004032:Diet; D004734:Energy Metabolism; D006801:Humans; D008610:Menthol / Q000737:chemistry*; D008962:Models, Theoretical; D009765:Obesity / Q000150:complications / Q000628:therapy*; D010641:Phenotype; D015995:Prevalence; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000378:metabolism; D022722:Thermogenesis; D000071256:Uncoupling Protein 1 / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D000071256:Uncoupling Protein 1; D008610:Menthol
keywords: Brown adipose tissue; Metabolism; Obesity; Overweight; TRPA1; TRPM8; Thermogenesis; UCP1; White adipose tissue; l-Menthol