Bartelt, Alexander

Chondronikola, Maria

Vidal-Puig, Antonio

Virtanen, Kirsi A

PubMed

Chondronikola, M.

Bartelt, A.

Vidal-Puig, A.

Virtanen, K.A.

PuSH

Editorial: Brown adipose tissue: From heat production in rodents to metabolic health in humans.

Apollo (Cambridge)

Frontiers in Endocrinology | www.frontiersiEdited and reviewed by:Cunming Duan,University of Michigan, United States*Correspondence:Maria Chondronikolamchondr@ucdavis.eduSpecialty section:This article was submitted toExperimental Endocrinology,a section of the journalFrontiers in EndocrinologyReceived: 09 July 2021Accepted: 14 July 2021Published: 26 July 2021Citation:Chondronikola M, Bartelt A,Vidal-Puig A and Virtanen KA (2021)Editorial: Brown Adipose Tissue:From Heat Productionin Rodents to MetabolicHealth in Humans.Front. Endocrinol. 12:739065.doi: 10.3389/fendo.2021.739065EDITORIALpublished: 26 July 2021doi: 10.3389/fendo.2021.739065Editorial: Brown Adipose Tissue:From Heat Production in Rodents toMetabolic Health in HumansMaria Chondronikola1,2*, Alexander Bartelt 3,4,5,6, Antonio Vidal-Puig7,8and Kirsi A. Virtanen9,10,111 Department of Nutrition, University of California Davis, Davis, CA, United States, 2 Department of Nutritional Sciences andDietetics, Harokopio University of Athens, Athens, Greece, 3 Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany, 4 German Center for Cardiovascular Research, Partner Site Munich Heart Alliance,Munich, Germany, 5 Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for EnvironmentalHealth, Neuherberg, Germany, 6 Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston,MA, United States, 7 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MedicalResearch Council, Metabolic Diseases Unit, Cambridge, United Kingdom, 8 Wellcome Trust Sanger Institute, Hinxton,United Kingdom, 9 Turku PET Centre, Turku University Hospital, Turku, Finland, 10 Department of Public Health and ClinicalNutrition, University of Eastern Finland, Kuopio, Finland, 11 Department of Endocrinology and Clinical Nutrition, KuopioUniversity Hospital, Kuopio, FinlandKeywords: adipose tissue, brown, metabolism and obesity, thermogenesis, adipose tissue beigeingEditorial on the Research TopicBrown Adipose Tissue: From Heat Production in Rodents to Metabolic Health in HumansINTRODUCTIONThe unequivocal demonstration of functional brown adipose tissue (BAT) in adult humans (1–3)has led to a surge of scientific interest in its role in metabolic health. More recently, the discoverythat white adipose tissue (WAT) can adopt a phenotype similar to BAT (a process also known asbrowning or beigeing of WAT) (4) has further fueled the hope to exploit the powers of thermogenicadipocytes against the obesity-related metabolic disorders. One of the unique characteristics of thethermogenic adipocytes is the large number of mitochondria enriched in uncoupling protein 1(UCP1), which hotwires oxidative phosphorylation resulting in thermogenesis (5). Upon activation(in response to neuroendocrine, metabolic or dietary factors), thermogenic adipocytes increase theirmetabolic rate, oxygen consumption and accelerate glucose, lipid, and branched-chain amino acidmetabolism (6). BAT has also been implicated as a potential endocrine organ, affectingthe metabolic activity of distant tissues to coordinate whole-body metabolism (7). Althoughresearch efforts to this date have improved the current understanding of the regulation andmetabolic significance of BAT and the thermogenic adipocytes, many questions remain to beanswered. The manuscripts included in this Research Topic: i) summarize the current knowledge onthe origins and plasticity of the thermogenic adipocytes and their potential role in metabolic health,ii) provide mechanistic insights on pathways implicated in thermogenesis, and iii) discuss currentresearch gaps and how those can be addressed in the future.n.org July 2021 | Volume 12 | Article 7390651Chondronikola et al. Editorial: BAT and Metabolic HealthMOLECULAR MECHANISMS FOR THEMAINTENANCE OF THE THERMOGENICADIPOCYTESIn this Research Topic, Rabbie summarizes the current knowledgeon the origins of thermogenic adipocytes (8). This review alsoprovides a comprehensive overview of the transcriptional andepigenetic factors involved in their development and maintenance.The author emphasizes the need for future research to improve thecurrent understanding of the mechanisms involved in the bi-directional transition between the thermogenic adipocytes and theclassical white adipocytes.THE ROLE OF BAT IN HUMANMETABOLISMThe role of BAT in metabolic health is currently a topic of majorscientific interest and debate. Pan et al. summarize the differencesbetween rodent and human BAT, the methods for the assessmentof human BAT, and the pathways regulating BAT thermogenesis(Pan et al.). McNeill et al. review the current evidence onsubstrate utilization by human BAT. Advanced medicalimaging techniques and microdialysis have been used to assesssubstrate utilization in BAT. BAT has high capacity for plasmaglucose and free and dietary fatty acid uptake especially inresponse to cold, while BAT also utilizes intracellulartriglycerides for thermogenesis. Additionally, intermediatemetabolites (i.e., pyruvate and lactate) and glutamate may fuelBAT thermogenesis and/or play a role in the regulation of BAT.Limitations of the currently available methods hinder the effortsto further understand substrate utilization by BAT further.MECHANISTIC INSIGHTS IN THEREGULATION OF ADIPOSE TISSUETHERMOGENESISElectrical Neurostimulation (EN) for theActivation of BATAlthough the role of the nervous system and adrenergic signalingin the regulation of BAT metabolism is well-established (5), thecurrently available b-adrenergic agonists lack tissue-specificity,limiting their clinical utility due to cardiovascular side effects (8).Li et al. reported that EN of BAT in rodents increased BATthermogenesis and decreased its intracellular lipid content,whereas b3-adrenergic blockade prevented the stimulation ofBAT thermogenesis, suggesting that EN acts via beta3-adrenergic signaling (Li et al.). EN is a novel tissue-specificapproach for the activation of BAT without the cardiovascularside effects of the systemic b-adrenergic stimulation.The Role of Macrophages in BATThermogenesisAlthough resident immune cells in BAT have been implicated inthe regulation of BAT, their role remains debatable (9). Fischeret al. reported that thermoneutrality led to pronouncedFrontiers in Endocrinology | www.frontiersin.org 2macrophage infiltration of BAT, while cold exposure had theopposite effect (Fischer et al.). Moreover, exposure tothermoneutrality or room temperature conditions before a coldchallenge did not affect the cold-induced transcriptomicresponse in BAT suggesting that the presence of macrophagesin BAT may not affect thermogenesis. Future investigationsare needed to assess the role of macrophages in BATfunction comprehensively.Calsyntenin3b Regulation in BATRecent results from studies in rodents support that theneurotrophic and thermogenic calsyntenin3b-S100b axisregulates innervation in thermogenic adipose tissue (10).Plucinska et al. characterized the enrichment patterns ofcalsyntenin3b in various adipose tissue depots (Plucińska et al.).In humans, calsyntenin3b gene expression was higher in theperirenal multilocular BAT depot than the subcutaneous WAT,while its expression was positively associated with UCP1expression. In rodents, calsyntenin3b gene expression waspreferentially enriched in BAT and the enrichment pattern wassensitive to various physiological challenges (i.e., cold exposure,rewarming, and obesity). Calsyntenin3b is a promising target forthe regulation of adipose-to-neuro axis.IN VITRO MODELS FOR THE STUDY OFHUMAN BATTo this date, studies in animal models have been the primarysource of knowledge on the cellular identity, plasticity, metabolicregulation and significance of the thermogenic adipocytes.However, this classic experimental approach does not accountfor interspecies differences between humans and rodents.Considering the high cost and limitations of clinical research, itis essential to establish efficient preclinical methods for studying ofthe thermogenic adipocytes. Smartly designed in vitro experimentscan be used in conjunction with in vivo studies to address the openquestions in the thermogenic adipocyte biology. Samuelson andVidal-Puig reviewed the current methods studying of human BATin vitro including immortalizing primary human brownadipocytes, multipotent stem cells, and human pluripotent stemcells and the advantages and limitations of each method(Samuelson and Vidal-Puig). Optimization of the current invitro models to more closely recapitulate the in vivo micro-environment of the thermogenic adipocytes (e.g., innervation,vascularization, extracellular matrix, presence of other cells, andtissue architecture) is of paramount importance to acceleratescientific progress in realizing the role of BAT in the context ofthe obesity-related metabolic complications.CONCLUSIONBAT and thermogenic adipocytes constitute emerging targetsagainst obesity and its related metabolic diseases that affect thewell-being and quality of life of millions of people worldwide. Tothis date, the research progress on better understanding theorigins, metabolic regulation and significance of BAT and theJuly 2021 | Volume 12 | Article 739065Chondronikola et al. Editorial: BAT and Metabolic Healththermogenic adipocytes has been substantial. Nevertheless, manyquestions remain open. The most critical rate-limiting bottleneckhindering the scientific progress in the field of human BAT is thelack of tools to efficiently establish the signaling pathwaysregulating adipose tissue thermogenesis and to understand itsmetabolic significance at the tissue-specific and whole-body level.Answering those questions is critical to establish the thermogenicadipose tissue as a therapeutic target against metabolic disease.AUTHOR CONTRIBUTIONSMC and KV wrote the manuscript. AVP and AB edited themanuscript. All authors contributed to the article and approvedthe submitted version.Frontiers in Endocrinology | www.frontiersin.org 3FUNDINGMC is supported by the USDA National Institute of Foodand Agriculture, Hatch project number CA-D-NTR-2618-H.AB was supported by the Deutsche ForschungsgemeinschaftSonderforschungsbereich 1123 (B10), a Deutsches Zentrumfür Herz-Kreislauf-Forschung Junior Research GroupGrant, and the European Research Council StartingGrant PROTEOFIT.ACKNOWLEDGMENTSWe are grateful to all the authors and reviewers for theircontributions to this Research Topic.REFERENCES1. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al.Identification and Importance of Brown Adipose Tissue in Adult Humans.N Engl J Med (2009) 360:1509–17. doi: 10.1056/NEJMoa08107802. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al.Functional Brown Adipose Tissue in Healthy Adults. N Engl J Med (2009)360:1518–25. doi: 10.1056/NEJMoa08089493. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, DrossaertsJM, Kemerink GJ, Bouvy ND, et al. Cold-Activated Brown Adipose Tissue inHealthy Men.N Engl J Med (2009) 360:1500–8. doi: 10.1056/NEJMoa08087184. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. BeigeAdipocytes are a Distinct Type of Thermogenic Fat Cell in Mouse andHuman. Cell (2012) 150:366–76. doi: 10.1016/j.cell.2012.05.0165. Cannon B, Nedergaard J. Brown Adipose Tissue: Function and PhysiologicalSignificance. Physiol Rev (2004) 84:277–359. doi: 10.1152/physrev.00015.20036. Chondronikola M, Sidossis LS. Brown and Beige Fat: From Molecules toPhysiology. Biochim Biophys Acta Mol Cell Biol Lipids (2019) 1864:91–103.doi: 10.1016/j.bbalip.2018.05.0147. Gavaldà-Navarro A, Villarroya J, Cereijo R, Giralt M, Villarroya F. TheEndocrine Role of Brown Adipose Tissue: An Update on Actors and Actions.Rev Endocrine Metab Disord (2021). doi: 10.1007/s11154-021-09640-68. Chen KY, Brychta RJ, Abdul Sater Z, Cassimatis TM, Cero C, Fletcher LA,et al. Opportunities and Challenges in the Therapeutic Activation of HumanEnergy Expenditure and Thermogenesis to Manage Obesity. J Biol Chem(2020) 295:1926–42. doi: 10.1074/jbc.REV119.0073639. Villarroya F, Cereijo R, Villarroya J, Gavaldà-Navarro A, Giralt M. Towardan Understanding of How Immune Cells Control Brown and BeigeAdipobiology. Cell Metab (2018) 27:954–61. doi: 10.1016/j.cmet.2018.04.00610. Zeng X, Ye M, Resch JM, Jedrychowski MP, Hu B, Lowell BB,et al. Innervation of Thermogenic Adipose Tissue via a Calsyntenin3b–S100b Axis. Nature (2019) 569:229–35. doi: 10.1038/s41586-019-1156-9Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2021 Chondronikola, Bartelt, Vidal-Puig and Virtanen. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that theoriginal publication in this journal is cited, in accordance with accepted academicpractice. No use, distribution or reproduction is permitted which does not comply withthese terms.July 2021 | Volume 12 | Article 739065

Editorial: Brown Adipose Tissue: From Heat Production in Rodents to Metabolic Health in Humans.

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Editorial: Brown Adipose Tissue: From Heat Production in Rodents to Metabolic Health in Humans.

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