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Aalborg Universitet Effect of habitual cold exposure on brown adipose tissue activity in Arctic adults a systematic review Motzfeldt Jensen, Mette; Jørgensen, Martin Grønbech; Elberling Almasi, Charlotte; Andersen, Stig Published in: International Journal of Circumpolar Health DOI (link to publication from Publisher): 10.1080/22423982.2025.2545059 Creative Commons License CC BY-NC 4.0 Publication date: 2025 Document Version Publisher's PDF, also known as Version of record Link to publication from Aalborg University Citation for published version (APA): Motzfeldt Jensen, M., Jørgensen, M. G., Elberling Almasi, C., & Andersen, S. (2025). Effect of habitual cold exposure on brown adipose tissue activity in Arctic adults: a systematic review. International Journal of Circumpolar Health, 84(1), Article 2545059. https://doi.org/10.1080/22423982.2025.2545059 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. - Users may download and print one copy of any publication from the public portal for the purpose of private study or research. - You may not further distribute the material or use it for any profit-making activity or commercial gain - You may freely distribute the URL identifying the publication in the public portal - Take down policy If you believe that this document breaches copyright please contact us at vbn@aub.aau.dk providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from vbn.aau.dk on: January 08, 2026

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Effect of habitual cold exposure on brown adipose tissue activity in Arctic adults: a systematic review Mette Motzfeldt Jensen a,b, Martin Grønbech Jørgensen a,c, Charlotte Elberling Almasi a,d and Stig Andersen a,b,c aDepartment of Clinical Medicine, Aalborg University, Aalborg, Denmark; bGreenland Center for Health Research, Ilisimatusarfik, University of Greenland, Nuuk, Greenland; cDepartment of Geriatric Medicine, Aalborg University Hospital, Aalborg, Denmark; dDepartment of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark ABSTRACT Brown adipose tissue (BAT) is crucial for non-shivering thermogenesis, a key adaptation for humans in Arctic environments. The discovery of BAT presence in human adults has ignited curiosity due to its potential role in combating obesity, type II diabetes and cardiovascular diseases. Following PRISMA guidelines and preregistration (PROSPERO CRD42023444511) this systematic review aims to describe the evidence of BAT activity among adults living in the Arctic with habitual cold exposure. Systematic searches were conducted in PubMed, Embase, and Scopus as of November 2024. In addition, trial registration searches, manual screening of reference lists, and requests to experts were performed. No restrictions were made regarding study selection. Each study was assessed using the NIH Quality Assessment Tool for Observational Cohort and Cross- Sectional Studies. Of 429 studies screened, 21 full texts were included for eligibility assessment, and eight studies qualified for inclusion. Due to the heterogeneity of the included studies, a meta-analysis was not pursued. Results indicate high BAT activity in Arctic populations, as supported by increased supraclavicular skin temperatures after cold exposure, thyroid hormone dynamics, and genetic markers linked to BAT. Findings highlight BAT’s role in cold adaptation among adults residing in Arctic regions, though methodological limitations remain, necessitating further research. ARTICLE HISTORY Received 7 February 2025 Revised 9 July 2025 Accepted 4 August 2025 KEYWORDS Brown adipose tissue; cold adaptation; Arctic populations; non-shivering thermogenesis; infrared thermography; genetic adaptation; thermoregulation Introduction Brown adipose tissue (BAT) is a metabolically active adipose tissue with the ability to generate heat through non-shivering thermogenesis. Unlike white adipose tissue, which functions primarily in energy storage, BAT is rich in mitochondria containing uncoupling protein 1 (UCP1). Through UCP1-mediated uncoupling of oxidative phosphorylation, BAT dissipates energy as heat, facilitating thermogenesis without muscular activity. Historically, BAT was thought to be limited to hibernating mammals and human infants, however, accumulating evidence in recent years has demonstrated that some human adults maintain functional BAT [1,2]. In adult humans, BAT is located in the cervical, supraclavicular, axillary, mediastinal, parasternal, and abdominal regions. Among these, the supraclavicular depot is the most consistently identified and exhibits the highest metabolic activity [3]. Owing to its superficial anatomical position, changes in skin temperature over this region during cold exposure are frequently interpreted as indirect indicators of BAT activation [4]. Adult BAT presence seems to vary across study populations and may be influenced by biological and lifestyle factors, including age, sex, and BMI [5,6]. Active BAT enhances energy expenditure and may play a role in glucose and lipid homoeostasis, suggesting a protective role in cardiometabolic disease, including reduced risks of obesity, type 2 diabetes, and related metabolic disorders [7]. CONTACT Mette Motzfeldt Jensen mette.motzfeldt@hotmail.com Department of Clinical Medicine, Aalborg University, 9000 Aalborg, Denmark Supplemental data for this article can be accessed online at https://doi.org/10.1080/22423982.2025.2545059 INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH 2025, VOL. 84, NO. 1, 2545059 https://doi.org/10.1080/22423982.2025.2545059 © 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4. 0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

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BAT activation is triggered by cold exposure through thyroid hormones, which play a key role in the full activation of thermogenesis [8]. Cold exposure stimulates the sympathetic nervous system, leading to norepinephrine release, which activates UCP1 in BAT cells. Thyroid hormones, particularly triiodothyr onine (T3), enhance the mitochondrial activity in BAT tissue, thus amplifying the thermogenic response [9]. BAT activity can be assessed through both direct and indirect methods. Direct measurement techniques include fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT), which identifies active BAT by tracking glucose uptake in response to cold exposure. Due to its expense and radiation exposure, PET/CT is often replaced by indirect methods. Such indirect measurements include infrared thermography (IRT) to assess skin temperature over supraclavicular regions Additional methods include measuring circulating thyroid hormone levels, and genetic analyses of BAT-related genes such as genes for UCP1. Most research on BAT has been conducted in populations living in temperate climates, offering experi mental cold exposure. While these studies have provided valuable insights, they do not fully capture the role of BAT in populations for whom cold exposure is a recurrent and prerequisite part of daily life. Populations residing in inherently cold climate offer a unique opportunity to explore how environmental cold conditions influence the importance of BAT. Arctic populations face exposure to extreme cold as an integral part of daily life, and BAT may play a pivotal role in adaptation to maintain body temperature. By focusing on populations to whom cold is a habitual factor rather than an experimental condition, this systematic review aims to assess the current state of research on BAT activity in Arctic populations, and hence contribute to understanding how environmental factors shape adaptive thermogenesis. Methods This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10]. The review protocol was registered in PROSPERO before the study was initiated (registration number: CRD42023444511). Eligibility criteria Eligible studies included original research on Arctic adult populations living in permafrost regions, reporting direct or indirect measurement of BAT activity as either a primary or secondary outcome. The primary outcomes for this review were direct measurements of BAT presence and activity, specifically through biopsies or PET/CT scans or similarly advanced imaging techniques. Secondary outcomes included any indirect measurement of BAT activity, such as skin temperature measurements at anatomical sites with superficial BAT deposits, hormone levels indicating metabolic activity associated with BAT, or genetic markers linked to BAT activation. Setting criteria were specified as regions with permafrost and an Arctic climate, defined by an annual mean temperature below 0°C and no month with an average temperature above 10°C, ensuring that participants were consistently exposed to habitual cold conditions. Eligible studies could involve additional short-term cold exposure to trigger BAT activity before measurement. Articles were excluded if they did not meet all inclusion criteria, such as studies focusing on non-Arctic populations, children, or those using only short-term cold exposure as the primary condition. All study designs were included, and no language or publication date restrictions were applied. Search and screening A comprehensive search of the PubMed, Embase, and Scopus databases was conducted, using search terms related to BAT and Arctic populations. The search strategy was developed in collaboration with an experi enced research librarian from Aalborg University Hospital, Denmark. Keywords such as “Beige and Brown Adipose Tissue” and “Arctic” were combined using Boolean operators (e.g. AND, OR) to capture relevant studies comprehensively. The full list of search terms is available in the supplementary material (S1). The initial search was conducted in March 2023 and updated in November 2024. A final hand search of the reference lists was performed to identify any additional studies. 2 M. MOTZFELDT JENSEN ET AL.

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Title and abstract screening were completed using Covidence, with two independent reviewers (M.M. and S.A.) conducting the initial screening based on relevance to BAT activity in Arctic populations. Full-text screening was conducted independently by both reviewers, and any discrepancies were resolved through consensus. Consensus was reached and there was no need to consult with the third party at this stage. Data extraction Data were extracted using a standardised form to systematically collect information on the study such as population characteristics, BAT measurement methods, and outcomes. Two independent reviewers (M. M. and S.A.) extracted the data, and any discrepancies were resolved through consensus or by consulting a third reviewer (M.G.J.). Quality assessment The quality of included studies was evaluated as good, fair, or poor using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [11]. Studies were assessed based on criteria such as population definition, sample size justification, exposure assessment, and control for confounding factors. The assessment criteria and guidance can be accessed through the NIH website [11]. Quality assessment was conducted independently by two reviewers (M.M. and S.A.), with a third reviewer (M.G.J) involved to resolve any discrepancies. Since one of the independent reviewers (S.A.) is the first author of one of the included studies, a fourth reviewer from a different department (C.A.) was invited to independently assess the quality of that report to avoid potential conflicts of interest. Results Search outcome A total of 429 studies were identified, and eight met the inclusion criteria (Figure 1). These studies investigated BAT activity indirectly through skin temperature imaging, thyroid hormone levels, and genetic markers in Arctic populations. Study characteristics All included studies were observational. Six studies were conducted in Russia, primarily focusing on Yakutsk in Northern Siberia [12–17]; one of these studies also included a Midwestern comparator population near Chicago in the United States of America [15]. One study was conducted in Greenland, with settings covering the largest city in West Greenland and a smaller town and settlements in East Greenland [18]. The final study was conducted in Finland, within the reindeer herder districts in Lapland [19]. The study settings and key characteristics are summarized in Table 1. None of the included studies used direct measurements of BAT presence or activity. All used various indirect measures to infer BAT activity and highlight the physiological, hormonal, and genetic underpinnings of cold adaptation. The methods applied in the included studies are summarised below, along with their reported findings. Thermal imaging Four papers reported the use of IRT to assess the skin temperature in the supraclavicular area as a proxy for BAT activity [13–15,19]. Each study included baseline imaging followed by a second image after 30 minutes of cold exposure using water-perfused cooling suits to activate BAT. Across all studies, supraclavicular skin temperature (SST) was either maintained or increased relative to a reference skin temperature. Levy et al. 2018 reported stable SST after cooling exposure while the skin temperature of a reference point on the sternum declined significantly (p < 0.001), indicating the presence of active BAT among Yakut adults [13]. Compared to participants in Evanston USA, Levy et al. 2022 found significantly warmer SST compared to sternal temperatures (p < 0.001) in both the Yakutsk and the Evanston sample, however, Yakut had INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH 3

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significantly greater change in SST (p = 0.015) compared to the Evanston sample [15]. Similarly, among reindeer herders in sub-Arctic Finland, participants maintained higher SST compared to the sternal region [19]. Finally, Levy et al. 2021 explored the potential of a plasticity period during childhood by examining associations between adult SST and early-life environmental exposures. SST was measured in adulthood as a proxy for BAT activity and compared to ambient temperatures and outdoor activities during gestation, infancy, early childhood, middle childhood, and adolescence. BAT thermogenesis in adults was significantly associated to average temperatures (p = 0.021) and number of times participants experienced temperatures below −40 °F (p = 0.026). Adults who spent greater outdoor activities between ages five and seven exhibited significantly greater BAT thermogenesis (p = 0.037), and 11–13 age groups (p = 0.023). Trends towards similar associations were observed across additional age groups [14]. Indirect calorimetry Three of the studies using IRT to measure BAT thermogenesis also employed indirect calorimetry to measure energy expenditure [13,15,19]. This method estimates metabolic rate based on oxygen consumption (VO₂) and carbon dioxide production (VCO₂), allowing calculation of total and basal energy expenditure [20]. Figure 1. Flow diagram illustrating the study selection process for this systematic review. The diagram details the number of records identified, screened, excluded, and ultimately included based on the eligibility criteria. 4 M. MOTZFELDT JENSEN ET AL.

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Among reindeer Herders in Finland, cold exposure induced a significant mean increase of 8.7% in metabolic rates, however, a high degree of interindividual variation from −13.7% to + 35.0% was reported [19]. Yakut adults exhibited increased energy expenditure after cold exposure, and participants with greater BAT thermogenesis also had a larger percent change in energy expenditure after cooling [13]. Additionally, resting metabolic rates were higher in Yakut participants compared to those from Evanston [15]. Endocrine biomarkers Thyroid hormones, which play a critical role in BAT activation, were assessed in a cross-sectional study of different populations in Greenland. Free triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH) and thyroglobulin (TG) levels measured in serum and analysed in sub-populations of ethnicity; Greenlandic Inuit and Caucasian Danes, area of residency, and occupation as a proxy for degree of habitual cold exposure. Greenlandic Inuit men and women exposed to habitual cold demonstrated higher serum TG and altered T3 levels in sub-populations with the highest exposure to cold compared to popula tions living in larger towns and work indoor [18]. The findings supported functioning BAT as TG levels are elevated with thyroid activity and increased production rate of thyroid hormones. The parallel decrease in T3 levels in serum may indicate a high turnover of the hormone, utilised as a fuel source for BAT activity [18]. Furthermore, Nikanorava et al. 2020 and 2022 investigated levels of the adipokine; leptin and the myokine; irisin in Siberian populations and connecting these to genes possibly related to thermogenesis, described below. Genetic analyses These studies examined variants in genes associated with thermoregulation, lipid metabolism and hormonal pathways linked to BAT function. Genetic variants associated with cold adaptation were reported at higher frequencies in Arctic popula tions than in those from more southern regions [12,16,17]. Hallmark et al. analysed genomic data from Siberian populations to identify signals of adaptation to cold climate. Missense mutations in three genes involved in lipid metabolism relevant to BAT activity; phospho lipase A2 group IIA (PLA2GA), perilipin 1 (PLIN1) and angiopoietin-like protein 8 (ANGPTL8), were reported [12]. Nikanorova et al. analysed circulating irisin levels and polymorphisms in UCP1, UCP2, and UCP3 in residents of the coldest regions of Siberia.The elevated irisin levels linked to one significant UCP3 variant (rs1800849 polymorphism) were significant in women [17]. This SNP showed signals consistent with natural selection for cold-climate adaptation [17]. Similar sex-specific patterns were seen in the relationship between leptin levels and thermogenesis- related gene variants [16]. Leptin levels were assessed in connection to genes potentially involved in non- shivering thermogenesis (UCP1, UCP2, UCP3, BDNF among others). The TT genotype of UCP1 rs3811787 and the GG genotype of BDNF rs6265 were significantly associated with elevated leptin levels in females [16]. Among these, the UCP1 rs3811787 variant showed the strongest signal of cold climate adaptation, with the T-allele increasing in frequency across populations inhabiting more northern latitudes [16]. Quality assessment results Common limitations are the lack of sample size justification, time frame, and outcome assessments (Table 2), as indirect measurements BAT activity by use of IRT have not been sufficiently validated. Some studies underwent quality assessment twice because they comprised both chronic cold exposure and additional short-term cold exposure. Discussion The studies included in this review corroborate the presence and activity of BAT in Arctic populations, with findings from thermal imaging, thyroid hormone patterns, and genetic analyses pointing to adaptations that may facilitate thermogenesis in extreme cold. Together these findings suggest a potential role for BAT in adaptive mechanisms among Arctic and circumpolar populations. INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH 5

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Several studies have provided indirect yet consistent findings that BAT is present in adults residing in areas with habitual cold exposure, where adaptation to extreme cold environments was a necessity. Some of the included studies support the assumption that BAT is more active in populations with greater habitual cold exposure compared to populations from temperate climates. For example, the Table 1. Characteristics of the included studies First author, year. Country and latitude Population N Sex Female: Male ratio Mean age (SD) or age range Exposure(s) Comparator Outcome Andersen et al. 2012 [18] Greenland. Nuuk 64.1° N, Tasiilaq and settlements 65.3°N Greenlandic Inuit (n = 434) Caucasian Danes (n = 94) and mixed ethnicity (n = 7) 535 226:309 50–69 y/o Habitual cold exposure by residence Subgroups in Greenland, based on ethnicity, residence, and profession Thyroid hormone levels (TSH, T3, T4) and thyroid gland activity measured as serum thyroglobulin levels. Hallmark et al. 2018 [12] Russia. Across Siberia Indigenous populations of Siberia; Yakuts, Evenks, Koryaks, among others. 732 N/R N/R Habitual cold exposure by residence N/A DNA samples. Allele frequency of specific genes associated with lipid metabolism and thermogenesis in relation to geographical distribution. Levy et al 2018 [13] Russia. Yakutia 62°N Healthy Yakut adults. 74 43:31 28 (8.5) Habitual cold exposure by residence and short-term cold exposure for 30 minutes with water perfused suit (10°C) N/A Change in SST assessed by IRT. BMR and energy expenditure by indirect caliometry. Levy et al. 2021 [14] Russia. Yakutia, 62° N Healthy Yakut adults 58 33:25 24.6 [7] Habitual cold exposure by residence and outdoor activities during childhood. Short term cold exposure for 30 minutes with water perfused suit (10°C) Subgroups based on cold exposure during childhood Change in SST measured with IRT, weather data, and surveys on amount of cold exposure during childhood Levy et al. 2022 [15] Russia. Yakutia, 62° N Evanston, USA 42°N Healthy Yakut adults (n = 72) and healthy adults from Evanston, USA (n = 54). 126 42:30 (Yakut) 40:14 (USA) 26.0 (8.5) 23.0 (4.9) Habitual cold exposure by residence and short-term cold exposure for 30 minutes with water perfused suit (10°C) Participants from Evanston, USA Change in SST assessed by IRT. BMR and energy expenditure by indirect caliometry Nikanorova et al. 2021 [16] Russia. Yakutia, 62° N Yakut 281 186:95 19.8 (0.75) Habitual cold exposure by residence N/A Leptin levels and DNA samples for non- shivering thermogenesis genes. Nikanorova et al. 2022 [17] Russia. Yakutia, 62° N Yakut 279 185:94 19.8 (2.03) Habitual cold exposure by residence N/A Irisin levels and DNA samples for uncoupling protein genes: UCP1, UCP2, and UCP3. Ocobock et al. 2022 [19] Finland. Lapland, 66.5°N Healthy adult reindeer herders from Finland 22 6:16 20–64 y/o Habitual cold exposure by residence and short-term cold exposure for 30 minutes with water perfused suit (10°C) N/A Change in SST assessed by IRT. BMR and energy expenditure by indirect caliometry. SST = Supraclavicular skin temperature. IRT: Infrared thermography. BMR = Basal metabolic rate. N/R: Not reported, N/A not applied. 6 M. MOTZFELDT JENSEN ET AL.

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study by Levy et al. found a higher thermogenetic response among the Yakut population compared to a midwestern American population [15]. This is further supported by Andersen et al. in a comparison of Greenlanders with different levels of habitual cold exposure based on either residence or profession, showing thyroid parameters suggestive of BAT activity among those most exposed to cold [18]. These thyroid hormone patterns in cold-acclimated populations align with previously reported changes in thyroid hormone production rate and turnover following cold exposure, labelled the “Polar T3 syn drome” [21] Genetic analyses demonstrated that selection for specific genetic markers was strongly associated with colder climates, as their prevalence increased with latitude in northern populations [12,16,17]. These markers are linked to metabolic regulation and BAT activity, suggesting a genetic adaptation that enhances thermo genesis and energy balance in cold environments. Hallmark et al. reported that ANGPTL8 is highly expressed in BAT and upregulated by cold exposure and thyroid hormones, suggesting a role in lipid mobilisation and thermogenic regulation [22,23]. PLIN1, involved in lipid droplet regulation, has been associated with beige fat development in murine models, indicating a potential role in recruitable thermogenic fat in humans [24,25]. PLA2G2A is required for mitochondrial uncoupling in BAT, highlighting its importance in heat production during cold exposure [26]. These genes collectively point towards molecular mechanisms that may underlie human cold adapta tion through BAT activity [14]. The spatial and population-genetic patterns of these variants suggest that they may have undergone positive selection in response to environmental pressures in cold regions. Levy et al. demonstrated that early-life cold exposure, particularly during childhood, may enhance BAT activity in adulthood, suggesting that developmental plasticity contributes to sustained thermo genic capacity later in life [12]. Cold exposure is among the most potent physiological stimuli for BAT activation, where it promotes cell proliferation, UCP1 expression and browning of white adipocytes [27,28]. This is further supported by murine models demonstrating that cold exposure during conception or early gestation leads to increased BAT volume and thermogenic gene expres sion in the offspring, indicating that early developmental exposure to environmental temperature may programme BAT abundance and function through epigenetic mechanisms [29]. A recent study in humans observed that individuals whose mothers conceived during cold seasons exhibit higher BAT activity [30]. These findings collectively suggest that early-life environmental cues can epigen etically prime progenitor cells towards a brown adipocyte lineage, thereby facilitating more efficient BAT recruitment and thermogenic function in adulthood. Thus, BAT function may be shaped by Table 2. Quality assessment of included studies using the NIH quality assessment tool for observational Cohort and cross- Sectional studies. Each column represents a specific quality assessment criterion. Authors, year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Rating Andersen 2012 Yes Yes No Yes No Yes Yes Yes No No Yes No N/A Yes Fair Hallmark, 2018 Yes No N/R NA No Yes Yes NA No No Yes No N/A No Poor Levy, 2018 (Chronic cold) Yes Yes N/R Yes No No Yes No Yes No Yes No N/A Yes Fair Levy, 2018 (Acute cold) Yes Yes N/R Yes No Yes Yes No Yes No Yes No N/A Yes Fair Levy, 2021 (Chronic cold) Yes Yes N/R Yes No Yes Yes Yes Yes Yes Yes No N/A No Fair Levy, 2021 (Acute cold) Yes Yes N/R Yes No Yes Yes No Yes No Yes No N/A No Fair Levy, 2022 (Chronic cold) Yes Yes N/R Yes No Yes Yes No Yes No Yes No N/A No Fair Levy, 2022 (Acute cold) Yes Yes N/R Yes No Yes Yes No Yes No Yes No N/A No Fair Nikanorova, 2021 Yes Yes N/R NA No No Yes Yes Yes No Yes No N/A No Poor Nikanorova, 2022 Yes Yes N/R NA No No Yes Yes Yes No Yes No N/A No Poor Ocobock, 2022 (Chronic cold) Yes Yes N/R Yes No No Yes No Yes No Yes No N/A No Poor Ocobock, 2022 (Acute cold) Yes Yes N/R Yes No Yes Yes No Yes No Yes No N/A No Fair N/A = Not applicable. N/R = Not reported. 1. Clearly defined research question. 2. Study population clearly specified and defined. 3. Participation rate of eligible participants at least 50%. 4. Sample size justification. 5. Exposure assessed before outcome. 6. Sufficient timeframe to observe an effect. 7. Different levels of exposure examined. 8. Exposure measured using valid and reliable methods. 9. Outcome measures clearly defined, valid, and reliable. 10. Blinding of assessors. 11. Loss to follow-up of less than 20%. 12. Key confounding variables measured and adjusted for. 13. Statistical methods appropriate for study design. 14. Other sources of bias considered. INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH 7

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a concert of genetic and environmental factors, further supporting its adaptive role in Arctic populations. Although the evidence is compelling, the results rely on indirect measurements of BAT activity. One paper examined BAT directly; however, it was excluded as it did not fully meet our setting criteria, being conducted in a region just below the Arctic threshold in Finland [31]. The excluded study performed a direct examina tion of BAT through biopsies in former outdoor workers compared to former indoor workers. The findings included BAT deposits around the neck in former outdoor workers, supporting the idea that cold exposure will lead to increased BAT deposits even in a sub-Arctic climate. Other studies were excluded due to being performed only with short-term cold and not populations residing in Arctic climates, or due to an absence of measurements of BAT activity (Supplementary S2). Limitations of included studies The studies included in this review provide valuable insights into BAT’s potential role in human adaptation to cold environments, however significant limitations in study quality and measurement methods necessitate cautious interpretation of the results. A key limitation of this review is the overall low methodological quality of the included studies. Studies had small sample sizes, lacked standardised methodologies for measuring BAT activity, and relied on indirect assessments such as infrared thermography, thyroid hormone levels, or genetic markers. While these methods provide valuable insights, they do not offer definitive proof of BAT presence or activity, making the findings more susceptible to bias and alternative interpretations. IRT, one of the most frequently used methods, has not been fully validated for BAT assessment [4,32]. Although supraclavicular skin temperature changes may suggest BAT activation, they can also be influenced by factors unrelated to BAT, such as local blood flow and ambient temperature. This makes it challenging to draw a clear link between observed temperature patterns and BAT activity. Several included studies rely heavily on this method, which, while non-invasive and accessible, does not provide a direct measure of BAT presence or thermogenic capacity. Changes in energy expenditure during cold exposure are commonly interpreted as evidence of BAT activation. This is supported by direct evidence from PET/CT scans showing that individuals with metabo lically active BAT exhibit significantly greater cold-induced energy expenditure compared to those without detectable BAT [33]. The included studies consistently demonstrated that individuals exhibiting higher thermogenic responses as assessed by IRT also showed greater increases in energy expenditure. This observation supports a potential association between IRT-defined thermogenesis and whole-body energy expenditure. However, indirect calorimetry lacks anatomical specificity and cannot reliably attribute increases in energy expenditure to BAT activity, as it is unable to distinguish between BAT-derived thermo genesis and other mechanisms such as shivering. The substantial variability in individual energy expenditure responses highlights the limitations of using energy expenditure alone to infer thermogenic activation. Thyroid hormones are crucial for BAT function; however, they are also involved in multiple metabolic processes [34]. Consequently, altered thyroid hormone levels could reflect broader metabolic adaptations than just BAT activation. Increased thyroid activity in Arctic populations cannot unequivocally confirm BAT involvement without direct assessments. Genetic analyses offer another indirect approach, identifying markers associated with BAT function. While these genetic markers suggest an evolutionary basis for cold adaptation, they do not provide real-time insights into BAT activation. Nikanorova et al. highlights a significant association between plasma irisin levels and one specific variant of UCP3 among a subgroup of females [17] pointing to a possible role of UCP3 in adaptive thermogenesis. However, it may not be directly linked to BAT activity in the same way as UCP1, the key regulator of thermogenesis in BAT. UCP3 is expressed in BAT, and this expression correlates with UCP1 levels [35]. However, studies have shown that UCP3 cannot substitute for UCP1 in driving thermogenesis. UCP3-deficient mice exhibited normal cold-induced thermogenic responses, indicating that UCP3 is not essential for BAT-mediated heat production [36]. Moreover, direct functional assays in isolated UCP1- deficient brown adipocytes, have shown that UCP3 cannot substitute for UCP1 in mediating adrenergic or fatty acid-induced thermogenesis [37]. Collectively, these findings underscore that UCP1 is uniquely required for physiologically effective thermogenic function [36,37]. 8 M. MOTZFELDT JENSEN ET AL.

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The physiological relevance of the association between UCP3 variants and irisin levels in females is speculative. Irisin is known to exert a broad range of biological effects, including the modulation and browning of adipose tissue, as demonstrated in several studies of rodents [38–40]. However, the translational potential of these findings to humans is unclear, as the role and efficacy of irisin in human physiology remain debated [41,42]. Furthermore, the significance of the finding of irisin and a UCP3 variant may be limited by the reliance on a single statistically significant association among many tests performed, raising the potential for type I error. The lack of significant associations with other genes more directly linked further weakens the argument for a robust connection with BAT. While the study adds valuable insights to the discussion of genetic and hormonal adaptations to extreme environments, the findings must be interpreted with caution in relation to BAT. Future research Future research would benefit from incorporating direct BAT assessments using imaging techniques such as PET/CT or PET/MR scans, to validate these findings and further elucidate BAT’s metabolic role. Such studies could also explore BAT’s implications for broader metabolic health, particularly as it relates to glucose and lipid metabolism, which are often linked with cardiometabolic risk. Given BAT’s unique role in non-shivering thermogenesis, understanding its full impact in Arctic populations could yield insights into metabolic adaptations and the broader health implications of BAT function. The variability in quality and methodology among the included studies highlights the need for future research employing direct measures of BAT, such as PET/CT imaging, to improve the reliability of findings. Direct imaging techniques, while costly and logistically challenging, could provide more robust evidence of the role of BAT in cold adaptation. Use of direct imaging techniques, however, might not be feasible in remote areas. This method requires access to advanced medical equipment and infrastructure that are typically unavailable in isolated regions, such as Arctic communities. Indirect methods to provide evidence of BAT activity becomes a feasible alternative, which can offer valuable insights into BAT activation and function. However, it is essential that such methods are validated against established methods like PET/CT, and proper validation ensures that the results from indirect measurements reflect BAT activity. By refining and standardising these indirect tech niques, BAT may be studied in remote populations contributing to a deeper understanding of its role in cold adaptation and metabolic regulation. Conclusion This systematic review suggests that BAT plays a key role in thermogenic adaptation in Arctic populations. However, all findings are based on indirect assessments, necessitating cautious interpretation. The reliance on IRT, hormonal markers, and genetic analyses highlights the need for direct imaging validation to confirm BAT’s physiological role. Future research should focus on integrating direct imaging techniques or validated indirect methods with larger cohorts to refine our understanding of BAT’s function in cold environments. Such studies could also provide insights into BAT’s influence on metabolic health in Arctic populations, with potential implications for broader human adaptation and disease prevention. Disclosure statement No potential conflict of interest was reported by the author(s). Funding This systematic review was carried out as part of a Ph.D. project supported by the Novo Nordisk Foundation [Grant No. 0064985]. No specific funding was received for this study. INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH 9

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Effect of habitual cold exposure on brown adipose tissue activity in Arctic adults: a systematic review

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