Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Diabetes Symposium: Browning of Adipose Tissue—What's New?

Human Brown Adipose Tissue: What We Have Learned So Far

  1. Matthias J. Betz1 and
  2. Sven Enerbäck2⇑
  1. 1Department of Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
  2. 2Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  1. Corresponding author: Sven Enerbäck, sven.enerback{at}medgen.gu.se.
Diabetes 2015 Jul; 64(7): 2352-2360. https://doi.org/10.2337/db15-0146
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Abstract

Brown adipose tissue (BAT) is a unique tissue that is able to convert chemical energy directly into heat when activated by the sympathetic nervous system. While initially believed to be of relevance only in human newborns and infants, research during recent years provided unequivocal evidence of active BAT in human adults. Moreover, it has become clear that BAT plays an important role in insulin sensitivity in rodents and humans. This has opened the possibility for exciting new therapies for obesity and diabetes. This review summarizes the current state of research with a special focus on recent advances regarding BAT and insulin resistance in human adults. Additionally, we provide an outlook on possible future therapeutic uses of BAT in the treatment of obesity and diabetes.

Introduction

During recent years, brown adipose tissue (BAT) has regained the attention of biomedical research. While previously thought to be negligible in adult humans, its presence and metabolic activity in this population was unequivocally demonstrated by several articles published in 2009 (1–4). BAT is a thermogenic tissue that allows small mammals to keep body core temperature constant at cold ambient temperatures without shivering. It differs markedly from white adipose tissue (WAT). While white adipocytes mainly consist of a single large lipid droplet and possess only a few mitochondria, brown adipocytes contain multiple lipid droplets per cell and are packed with mitochondria. BAT is densely innervated by the sympathetic nervous system (SNS) and is highly vascularized. In rodents and human infants, a major depot is found between the scapulae, and more depots exist along the great vessels and in the retroperitoneum (5,6). In short, the unique thermogenic capacity of the tissue is due to its high content of mitochondria and the expression of uncoupling protein 1 (UCP1) (Fig. 1). UCP1 is a proton channel within the inner mitochondrial membrane that, upon activation, short circuits the respiratory chain, thereby dissipating chemical energy as heat.

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Immunohistochemistry of human interscapular (top row), periadrenal BAT (middle row), and subcutaneous WAT (bottom row), demonstrating the high number of mitochondriae and UCP1 in BAT as opposed to WAT. UCP1 is stained green, and cytochrome c oxidase is stained orange. The merged image (right column) shows the perfect colocalization of the two proteins, and nuclei are stained red.

Cold receptors in the skin register cool ambient temperatures and relay the signal to hypothalamic centers that regulate body temperature (7). The efferent signal to BAT is conveyed by the SNS and its transmitter norepinephrine (8), which activates β3-adrenergic receptors and rapidly stimulates intracellular lipolysis. The released fatty acids fuel the respiratory chain and open UCP1, which dissipates the mitochondrial proton gradient as heat (9). In addition to its thermoregulatory function, BAT has been described to be activated by certain nutrients and high-calorie diets. In a classic experiment, Rothwell and Stock (10) showed that high-calorie diets (so-called “cafeteria diets”) led to the activation of BAT in rodents and thus contributed to diet-induced thermogenesis. It was speculated that this mechanism would protect the rodents, at least in part, from diet-induced obesity (10). While the contribution of BAT to cold-induced thermogenesis is generally undisputed, the concept of diet-induced thermogenesis as a function of BAT has been challenged in recent years because of conflicting study results (11–13).

Stimulation of β3-adrenergic receptors not only activates BAT thermogenesis in the short term, but also increases mitochondrial biogenesis and the expression of UCP1, and leads to growth of the tissue. Long-term adrenergic stimulation induces brown adipocytes in what otherwise were WAT depots, which contribute to thermogenesis (5). Thyroid hormone increases sensitivity toward adrenergic stimuli, and a high expression level of type 2 deiodinase (DIO2) is one of the distinctive features of BAT. DIO2 converts thyroxine (T4) into triiodothyronine (T3), which has a considerably higher affinity for the thyroid hormone receptors (THRs) and is crucial for the thermogenic function of BAT (14).

While the physiology and function of the tissue were widely elucidated during the 1970s and 1980s, remarkable discoveries regarding the molecular development and differentiation of the tissue and its prevalence in human adults were made during the last decade.

Origins of BAT and Two Types of BAT

Given the high amounts of intracellular lipids, a common lineage for white and brown adipocytes was suspected. Surprisingly, classic BAT was shown to develop from the central dermomyotome, which also gives rise to dorsal dermis and epaxial muscle (15). This finding was corroborated by lineage-tracing studies demonstrating that myocytes and brown adipocytes, but not white adipocytes, derive from precursor cells expressing Myf5, a gene encoding the myogenic regulatory factor MYF-5. Chronic adrenergic activation in cold-exposed rodents leads to the development of brown adipocytes in WAT depots (16), which contribute to the thermogenic capacity (17). While the animals initially need to rely on shivering in order to maintain normal body core temperature, BAT expansion leads to a gradual increase in nonshivering thermogenesis (5). These induced brown adipocytes have been called “recruitable,” “brite” (brown in white), or “beige” adipocytes, and the latter currently is the most widely used term. Beige adipocytes exhibit the same cell morphology as classic brown adipocytes and appear to be functionally equal (18), but do not originate from Myf5-expressing progenitors (19) and exhibit unique gene signatures that differ from those of classic brown adipocytes found in the interscapular BAT (20).

Of the many transcription factors involved in BAT differentiation, two deserve special attention: peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) and PR domain zinc finger protein 16 (PRDM16).

PGC-1α stimulates mitochondrial biogenesis and oxidative metabolism, and is crucial for the adaptions to cold exposure (21,22). Its expression is considerably increased by cold exposure, and its knockout in brown preadipocytes considerably blunts the increase in UCP1 upon adrenergic signaling (23). PRDM16 is a zinc finger protein that was shown to be preferentially expressed in brown adipocytes compared with white adipocytes. It acts as a transcription factor in conjunction with PGC-1α. The overexpression of PRDM16 in preadipocytes from WAT depots led to a full brown adipocyte phenotype (24), and its abrogation in preadipocytes from classic BAT depots causes the loss of the brown adipocyte phenotype and differentiation into myocytes (19). Moreover, it is also expressed in the subcutaneous WAT depot in which adrenergic stimuli can give rise to beige adipocytes, but not in epididymal WAT depots, which are resistant to “browning” (25).

(Re)discovery of BAT in Human Adults

The relevance of BAT for human newborns and infants had been acknowledged and undisputed for decades (26,27), and even the presence of BAT in human adults was demonstrated in autopsy studies more than 40 years ago (28). However, even though UCP1 had already been shown to be expressed in human adult BAT in the 1980s and 1990s (29–31), its functional role was less clear-cut. Because of findings in rodent models and observations of increased energy expenditure in response to β3-adrenergic agonists (32) and different responses to cold in lean versus obese humans (33), it was speculated that decreased BAT mass and activity might be implicated in the development of obesity and type 2 diabetes (34). At that time it was, however, not possible to unequivocally prove the metabolic activity in human adults (35–37).

The increasing clinical use of 2-deoxy-2-[fluorine-18]fluoro-d-glucose integrated with computed tomography (18F-FDG PET/CT) scanning for the detection and surveillance of cancer led to the observation of bilateral tracer uptake in supraclavicular area fat in a proportion of patients, especially during the cold season (38), which prompted the assumption that this tissue might in fact be active BAT (39). In 2009, three articles (1,3,4) published in parallel in the New England Journal of Medicine unequivocally demonstrated the presence of functional BAT in human adults. Cypess et al. (1) extensively reviewed almost 2,000 routine [18F]-FDG PET/CT scans and identified bilateral tracer uptake in >5% of patients. In a different group of patients undergoing surgery in the cervical region, they could identify UCP1+ multilocular adipocytes in the supraclavicular region (1). Using a different approach, van Marken Lichtenbelt et al. (3) demonstrated that the characteristic [18F]-FDG uptake in the supraclavicular region occurred in response to mild cold exposure in a group of healthy volunteers and was associated with an increase of thermogenesis, as determined by indirect calorimetry. A similar approach was used by Virtanen et al. (4), who additionally took biopsy specimens from the supraclavicular region, which had been PET positive in response to cold exposure and could unequivocally prove the BAT identity of this tissue. In the following years, these findings have been corroborated by numerous observational and prospective studies (40–48).

PET/CT imaging revealed active BAT in adult humans in the supraclavicular area, the retroperitoneum, and along the aorta, with the main depot in the supraclavicular area (2). In line with previous autopsy studies (28), there was no BAT depot in the interscapular area of adults. In analogy to the findings in animal models, it was speculated that the depots found in adult humans are of the beige BAT type and might thus not be equivalent to the classic interscapular BAT depot (49,50). Indeed, recent studies (51,52) using repetitive cold exposure demonstrate high plasticity of BAT in human adults. Additional evidence for a browning phenomenon comes from the fact that BAT was more likely to be found in the retroperitoneal tissue of patients undergoing adrenal surgery during the cold season (53).

Using a combination of MRI and molecular analysis, we could demonstrate that an interscapular BAT depot is found in human infants and consists of classic brown adipocytes, while the supraclavicular and retroperitoneal depots found in human adults show a molecular signature that is consistent with the beige type of brown adipocytes (54). Additionally, two other groups of investigators (55,56) independently identified both types of brown adipocytes in different depots of cervical BAT in human adults and thus corroborated our finding that human adults exhibit two types of BAT. Recently, a role for alternatively activated macrophages and eosinophils in the development of functional beige BAT has been reported in mice (57,58). Additionally, a population of brown adipocyte progenitors was identified in skeletal muscle in both mice (59) and humans (60,61). These cells could be differentiated into mature brown adipocytes by stimulation with bone morphogenetic protein (BMP) 7, thus presenting a potential target for pharmacological intervention in humans.

The presence of different brown adipocyte cell types in humans is conceptually important since they can possibly be targeted by different pharmacologic stimuli.

The Role of BAT in Insulin Resistance and Obesity Diabetes in Humans

The details of important studies on the role of BAT and obesity and insulin resistance in humans are given in Table 1.

View this table:
  • View inline
  • View popup
Table 1

Important studies investigating BAT and its relevance for obesity and insulin sensitivity/glucose metabolism in humans

Retrospective studies (1,42,46) using PET/CT data from large cohorts of humans demonstrated an inverse relationship between the presence of active BAT and obesity. However, the prevalence of BAT was low in these studies (5–10%) because BAT activity was not stimulated by cold exposure. Carefully designed studies (2,3) using mild cold exposure not only demonstrated active BAT in up to 95% of subjects, but could also corroborate the inverse association with BMI. Additionally, BAT prevalence and activity were much lower in patients with severe obesity (62), and BAT activity increased in this group after weight loss induced by bariatric surgery (63). Given the association of obesity and insulin resistance, it is not surprising that BAT activity was inversely associated with diabetes and fasting glucose level in observational studies (1,42,46).

It seems obvious that an energy-expending tissue—similar to exercising muscle—might have the potential to both counteract obesity and ameliorate insulin resistance. This notion is supported by several transgenic mouse models that exhibit increased BAT activity. Direct overexpression of UCP1 in WAT of C57BL/6J mice prone to obesity reduced body weight (64). Overexpression of the transcription factor FOXC2 in adipose tissue induced brown adipocytes in WAT depots. Transgenic animals were resistant to diet-induced obesity (65), intramuscular fatty acyl-CoA deposition, and diet-induced hepatic insulin resistance (66). While the interscapular BAT depot is a stable trait in rodents, the capacity to induce brown adipocytes in WAT depots when stimulated by cold or adrenergic agonists varies significantly between genetically different mouse strains. Interestingly, this ability is lowest in strains susceptible to obesity and diabetes (17,67,68). What exactly causes these variations and whether these observations can be translated to humans is yet to be revealed. Currently, few studies have investigated the association of BAT and genetic variation in humans. Single nucleotide polymorphisms in the human UCP1 and ADRB3 (adrenergic receptor 3β) genes were associated with increased age-related decline of BAT activity, as measured by FDG PET in healthy Japanese volunteers (69) and increased visceral fat in the same population (70).

Human BAT expresses high levels of the glucose transporter GLUT4, and insulin stimulates glucose uptake into the tissue to a similar degree as in muscle. In analogy to the noninsulin-dependent glucose uptake in exercising muscle, cold exposure leads to higher glucose uptake in BAT than does insulin stimulation (71). Consistent with these findings, a short-term mild cold stimulus increased insulin sensitivity in healthy volunteers with active supraclavicular BAT (72). Conversely, both the cold- and the insulin-activated glucose uptake into BAT were significantly lower in obese humans than in control subjects of normal weight (73). Decreased BAT activity could be a consequence of obesity or insulin resistance or an underlying metabolic phenotype. Interventional studies aiming to increase BAT mass and activity in humans, however, demonstrated increased glucose disposal and insulin sensitivity after repetitive cold exposure designed to increase BAT activity (51,74). Together with data obtained from rodent models, this evidence suggests that reduced BAT activity contributes to the development of obesity and insulin resistance.

Apart from effects on glucose metabolism, experiments in rodents also provide evidence for beneficial effects of active BAT on lipid metabolism. It should be pointed out that intracellular lipids are the main substrate of BAT thermogenesis during short-term cold exposure. In mice, the uptake of triglyceride-rich lipoproteins in BAT increased upon cold exposure through upregulation of lipoprotein-lipase and CD36 in the endothelium of its dense vasculature (75), thus contributing to triglyceride homeostasis. Ouellet et al. (40) could demonstrate consumption of intracellular lipids and increased uptake of fatty acids into cold-activated BAT in healthy human volunteers. Interestingly, in a mouse model of human-like lipoprotein metabolism, metformin was able to enhance the clearance of VLDL particles in BAT and also to increase BAT mitochondrial content and activity, suggesting potential implications of BAT in the actions of this widely used antidiabetic drug (76).

In summary, a role for BAT in glucose and lipid metabolism, and thus in the pathogenesis of the metabolic syndrome and type 2 diabetes, is supported by an increasing amount of evidence. It might thus constitute a valuable therapeutic target with which to treat metabolic disease in humans.

BAT as a Potential Drug Target To Treat Obesity and Diabetes in Humans

Obesity and its associated diseases lead to enormous human suffering and health care–related costs. Increasing energy expenditure by the expansion and activation of BAT could potentially help reduce body weight and improve insulin sensitivity, especially in those who are not able to increase energy expenditure through muscular activity. Figure 2 summarizes the physiological pathway leading to BAT activation and expansion, effects on metabolism, and potential pharmaceutical approaches.

Figure 2
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2

BAT is activated upon cold exposure via the SNS. Thyroid hormones play an important role in the upregulation of thermogenesis, and their local activity is dramatically increased by DIO2. Several peptide hormones have been demonstrated to induce differentiation of beige BAT in WAT depots in mice. Potential pharmaceutical substances for BAT activation are placed next to their physiological targets and framed in red. Activation of BAT leads to beneficial effects on whole-body metabolism; the effects, denoted by *, have currently only been demonstrated in animal models. β3-AR, β3-adrenergic receptor; FGF, fibroblast growth factor; NEFA, nonesterified fatty acid.

The most straightforward approach would be to use catecholamine derivatives to stimulate BAT. While norepinephrine and related substances cannot be used in the therapeutic setting because of cardiovascular side effects, specific β3-adrenergic receptor agonists were successfully used in rodents to increase BAT activity, and ameliorate obesity and insulin resistance (77,78). In lean men, a β3-adrenergic agonist increased fat oxidation and insulin sensitivity, but it failed to alter energy expenditure after 8 weeks of use (79). Another β3-adrenergic receptor agonist could increase resting energy expenditure in the short term in healthy obese men (80). Extended treatment over 28 days reduced plasma triglyceride levels, but thermogenesis or body weight did not change (81). However, these studies were performed before the presence of active BAT in adult humans was acknowledged, and therefore BAT activity was not assessed directly.

Using [18F]-FDG PET/CT scanning, Cypess et al. (82) recently demonstrated that the short-term increase in energy expenditure due to a selective β3-adrenergic receptor agonist was due to BAT activity in healthy human volunteers. The equivocal results seen in previous studies might have been caused by the fact that BAT was not present in all studied individuals or by downregulation of adrenergic receptors in response to their long-term stimulation. The indirect sympathomimetic agent ephedrine was also shown to stimulate BAT thermogenesis in the short term in lean men (BMI 22 kg/m2, n = 9), but not in obese men (BMI 36 kg/m2, n = 9) (83). However, another study (84) in 10 healthy volunteers (mean BMI 24 kg/m2, 4 males/6 females) could not detect an ephedrine-mediated increase of BAT activity. Importantly, long-term administration of ephedrine over 4 weeks reduced BAT activity even in healthy young men (mean BMI 24 kg/m2, n = 23) (85), possibly as a result of adrenergic receptor downregulation.

BAT thermogenesis is markedly increased in humans who have hyperthyroidism (86). Supraphysiologic doses of thyroid hormones are associated with serious side effects, prohibiting their therapeutic use to reduce body weight. However, adverse symptoms such as tachycardia are mainly related to the activation of THRα. Selective targeting of THRβ, on the other hand, conferred resistance to diet-induced obesity by increased BAT activity and was well tolerated in rats (87,88). Additionally, in mice, bile acids have been shown to increase DIO2 expression by binding to TGR5, a Gs-protein–coupled transmembrane receptor, and thus to increase the local availability of triiodothyronine and energy expenditure (89,90). Data on BAT activity from human studies with THR agonists or bile acid derivatives are currently not available.

In recent years, numerous efforts have been made to identify substances and hormones that are able to expand and activate BAT, and a range of different hormones and molecules has been described, mainly in animal models. The overexpression of PGC-1α in muscle led to the discovery of a novel peptide hormone secreted by muscle in response to exercise, which increases the number of beige adipocytes in murine WAT depots. Exogenous administration of this peptide hormone, which was named “Irisin,” led to the browning of subcutaneous adipose tissue depots in mice (91). Irisin expression was shown to be correlated to exercise in humans in some, but not all, studies (92). A recent article (93) convincingly demonstrated, however, that shivering leads to an increase in Irisin levels in humans, and it might thus provide a link between shivering and nonshivering thermogenesis in response to cold. While the receptor for Irisin still needs to be discovered, it was recently shown that Irisin acts on adipocytes through mitogen-activated protein kinase p38 and the extracellular signal–related kinase-mitogen-activated protein kinase pathway (94). On the same lines, another peptide named meteorin-like (Metrnl) was identified as a factor induced in muscle by exercise and in adipose tissue by cold exposure (57). Its administration increased energy expenditure and improved glucose tolerance in mice through an eosinophil-dependent increase in interleukin-4 concentrations, resulting in adipose tissue macrophage activation.

β-Aminoisobutyric acid (BAIBA) is another substance secreted by myocytes overexpressing PGC-1α, and its plasma levels rise in response to exercise training in humans. The administration of BAIBA increased the expression of BAT-specific genes in WAT depots of mice, and peroxisome proliferator–activated receptor α was identified as a potential target. Energy expenditure in BAIBA-treated animals was higher than in placebo-treated animals, and insulin sensitivity was improved (95). BMP7 and BMP8B (96–98) and fibroblast growth factor 21 (93,99) have also been described as peptide hormones influencing BAT function and development in mice. Using a different approach, a recent screen for small molecules able to transform human white adipocytes to brown adipocytes in vitro revealed that the inhibitors of Janus kinase, tofacitinib and R406, consistently increased UCP1 expression and mitochondrial gene expression (100).

Analogs of Irisin and other peptide hormones, as well as small molecules might be promising pharmacologic options to expand and activate BAT, but their efficacy in humans still needs to be tested.

On a physiological basis, BAT could also be expanded and activated by mild cold stimuli. Repeated intermittent exposure of healthy Japanese men without detectable BAT at baseline (mean BMI 22 kg/m2, n = 12) to mild cold (17°C for 2 h/day) during 6 weeks recruited and expanded BAT, and led to a decrease in body fat mass (52). In a similar experiment, the reduction of ambient temperature from 24°C to 19°C resulted in a mean cold-induced increase in energy expenditure of 5%, and of BAT activity of 10% in 24 healthy volunteers (101). These environmental strategies are backed by the seasonal variation of BAT prevalence and UCP1 expression in human adults, with the highest amounts seen during the cold season (2,53). In analogy to the promotion of physical activity on a population-based level, slightly reducing indoor temperatures could potentially help the prevention of obesity.

In conclusion, increasing BAT mass and activity in order to increase energy expenditure represents a promising new therapeutic target for the treatment of both obesity and insulin resistance.

Article Information

Funding. M.J.B. was supported by a grant from the Goldschmidt-Jacobson Foundation, Basel, Switzerland. S.E. was supported by grants from the Swedish Research Council (2012-1652 and 2014-2516), the Knut and Alice Wallenberg Foundation, the Sahlgrenska University Hospital (LUA-ALF), the European Union (HEALTH-F2-2011-278373, DIABAT), the IngaBritt and Arne Lundgren Foundation, the Söderberg Foundation, and the King Gustaf V and Queen Victoria Freemason Foundation.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. M.J.B. and S.E. wrote, reviewed, and edited the manuscript. M.J.B. and S.E. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. This study was presented in abstract form at the 75th Scientific Sessions of the American Diabetes Association, Boston, MA, 5–9 June 2015.

  • Received January 29, 2015.
  • Accepted March 26, 2015.
  • © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

References

  1. ↵
    1. Cypess AM,
    2. Lehman S,
    3. Williams G, et al
    . Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509–1517pmid:19357406
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Saito M,
    2. Okamatsu-Ogura Y,
    3. Matsushita M, et al
    . High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009;58:1526–1531pmid:19401428
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. van Marken Lichtenbelt WD,
    2. Vanhommerig JW,
    3. Smulders NM, et al
    . Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500–1508pmid:19357405
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Virtanen KA,
    2. Lidell ME,
    3. Orava J, et al
    . Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518–1525pmid:19357407
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Cannon B,
    2. Nedergaard J
    . Brown adipose tissue: function and physiological significance. Physiol Rev 2004;84:277–359pmid:14715917
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Enerbäck S
    . Human brown adipose tissue. Cell Metab 2010;11:248–252pmid:20374955
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Tajino K,
    2. Hosokawa H,
    3. Maegawa S,
    4. Matsumura K,
    5. Dhaka A,
    6. Kobayashi S
    . Cooling-sensitive TRPM8 is thermostat of skin temperature against cooling. PLoS One 2011;6:e17504pmid:21407809
    OpenUrlCrossRefPubMed
  8. ↵
    1. Nakamura K,
    2. Morrison SF
    . Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 2007;292:R127–R136pmid:16931649
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Fedorenko A,
    2. Lishko PV,
    3. Kirichok Y
    . Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 2012;151:400–413pmid:23063128
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    1. Rothwell NJ,
    2. Stock MJ
    . A role for brown adipose tissue in diet-induced thermogenesis. Nature 1979;281:31–35pmid:551265
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    1. Kozak LP
    . Brown fat and the myth of diet-induced thermogenesis. Cell Metab 2010;11:263–267pmid:20374958
    OpenUrlCrossRefPubMedWeb of Science
    1. Betz MJ,
    2. Bielohuby M,
    3. Mauracher B, et al
    . Isoenergetic feeding of low carbohydrate-high fat diets does not increase brown adipose tissue thermogenic capacity in rats. PLoS One 2012;7:e38997pmid:22720011
    OpenUrlCrossRefPubMed
  12. ↵
    1. Fromme T,
    2. Klingenspor M
    . Uncoupling protein 1 expression and high-fat diets. Am J Physiol Regul Integr Comp Physiol 2011;300:R1–R8pmid:21048077
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. de Jesus LA,
    2. Carvalho SD,
    3. Ribeiro MO, et al
    . The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 2001;108:1379–1385pmid:11696583
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    1. Atit R,
    2. Sgaier SK,
    3. Mohamed OA, et al
    . Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol 2006;296:164–176pmid:16730693
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    1. Cousin B,
    2. Cinti S,
    3. Morroni M, et al
    . Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 1992;103:931–942pmid:1362571
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Guerra C,
    2. Koza RA,
    3. Yamashita H,
    4. Walsh K,
    5. Kozak LP
    . Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 1998;102:412–420pmid:9664083
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Lee P,
    2. Werner CD,
    3. Kebebew E,
    4. Celi FS
    . Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes (Lond) 2014;38:170–176pmid:23736373
    OpenUrlCrossRefPubMed
  18. ↵
    1. Seale P,
    2. Bjork B,
    3. Yang W, et al
    . PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008;454:961–967pmid:18719582
    OpenUrlCrossRefPubMedWeb of Science
  19. ↵
    1. Waldén TB,
    2. Hansen IR,
    3. Timmons JA,
    4. Cannon B,
    5. Nedergaard J
    . Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab 2012;302:E19–E31pmid:21828341
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Wu Z,
    2. Puigserver P,
    3. Andersson U, et al
    . Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999;98:115–124pmid:10412986
    OpenUrlCrossRefPubMedWeb of Science
  21. ↵
    1. Puigserver P,
    2. Wu Z,
    3. Park CW,
    4. Graves R,
    5. Wright M,
    6. Spiegelman BM
    . A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998;92:829–839pmid:9529258
    OpenUrlCrossRefPubMedWeb of Science
  22. ↵
    1. Uldry M,
    2. Yang W,
    3. St-Pierre J,
    4. Lin J,
    5. Seale P,
    6. Spiegelman BM
    . Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 2006;3:333–341pmid:16679291
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Seale P,
    2. Kajimura S,
    3. Yang W, et al
    . Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007;6:38–54pmid:17618855
    OpenUrlCrossRefPubMedWeb of Science
  24. ↵
    1. Seale P,
    2. Conroe HM,
    3. Estall J, et al
    . Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011;121:96–105pmid:21123942
    OpenUrlCrossRefPubMedWeb of Science
  25. ↵
    1. Merklin RJ
    . Growth and distribution of human fetal brown fat. Anat Rec 1974;178:637–645pmid:4856126
    OpenUrlCrossRefPubMedWeb of Science
  26. ↵
    1. Houstĕk J,
    2. Vízek K,
    3. Pavelka S, et al
    . Type II iodothyronine 5′-deiodinase and uncoupling protein in brown adipose tissue of human newborns. J Clin Endocrinol Metab 1993;77:382–387pmid:8393883
    OpenUrlCrossRefPubMedWeb of Science
  27. ↵
    1. Heaton JM
    . The distribution of brown adipose tissue in the human. J Anat 1972;112:35–39pmid:5086212
    OpenUrlPubMedWeb of Science
  28. ↵
    1. Garruti G,
    2. Ricquier D
    . Analysis of uncoupling protein and its mRNA in adipose tissue deposits of adult humans. Int J Obes Relat Metab Disord 1992;16:383–390
    OpenUrlPubMedWeb of Science
    1. Kortelainen ML,
    2. Pelletier G,
    3. Ricquier D,
    4. Bukowiecki LJ
    . Immunohistochemical detection of human brown adipose tissue uncoupling protein in an autopsy series. J Histochem Cytochem 1993;41:759–764
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Lean ME,
    2. James WP,
    3. Jennings G,
    4. Trayhurn P
    . Brown adipose tissue uncoupling protein content in human infants, children and adults. Clin Sci (Lond) 1986;71:291–297pmid:3757433
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Astrup A,
    2. Lundsgaard C,
    3. Madsen J,
    4. Christensen NJ
    . Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr 1985;42:83–94pmid:4014068
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Lean ME,
    2. Murgatroyd PR,
    3. Rothnie I,
    4. Reid IW,
    5. Harvey R
    . Metabolic and thyroidal responses to mild cold are abnormal in obese diabetic women. Clin Endocrinol (Oxf) 1988;28:665–673pmid:3254262
    OpenUrlCrossRefPubMed
  32. ↵
    1. Lean ME
    . Brown adipose tissue in humans. Proc Nutr Soc 1989;48:243–256pmid:2678120
    OpenUrlCrossRefPubMedWeb of Science
  33. ↵
    1. Astrup A,
    2. Bülow J,
    3. Madsen J,
    4. Christensen NJ
    . Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am J Physiol 1985;248:E507–E515pmid:3922230
    OpenUrlPubMed
    1. Budd GM,
    2. Brotherhood JR,
    3. Beasley FA, et al
    . Effects of acclimatization to cold baths on men’s responses to whole-body cooling in air. Eur J Appl Physiol Occup Physiol 1993;67:438–449pmid:8299616
    OpenUrlCrossRefPubMed
  34. ↵
    1. Cunningham S,
    2. Leslie P,
    3. Hopwood D, et al
    . The characterization and energetic potential of brown adipose tissue in man. Clin Sci (Lond) 1985;69:343–348pmid:2998687
    OpenUrlPubMed
  35. ↵
    1. Cohade C,
    2. Mourtzikos KA,
    3. Wahl RL
    . “USA-Fat”: prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT. J Nucl Med 2003;44:1267–1270
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Nedergaard J,
    2. Bengtsson T,
    3. Cannon B
    . Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444–E452pmid:17473055
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Ouellet V,
    2. Labbé SM,
    3. Blondin DP, et al
    . Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 2012;122:545–552pmid:22269323
    OpenUrlCrossRefPubMedWeb of Science
    1. Yoneshiro T,
    2. Aita S,
    3. Matsushita M, et al
    . Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 2011;19:13–16pmid:20448535
    OpenUrlCrossRefPubMed
  38. ↵
    1. Ouellet V,
    2. Routhier-Labadie A,
    3. Bellemare W, et al
    . Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab 2011;96:192–199pmid:20943785
    OpenUrlCrossRefPubMedWeb of Science
    1. Lee P,
    2. Zhao JT,
    3. Swarbrick MM, et al
    . High prevalence of brown adipose tissue in adult humans. J Clin Endocrinol Metab 2011;96:2450–2455pmid:21613352
    OpenUrlCrossRefPubMedWeb of Science
    1. Lee P,
    2. Swarbrick MM,
    3. Zhao JT,
    4. Ho KK
    . Inducible brown adipogenesis of supraclavicular fat in adult humans. Endocrinology 2011;152:3597–3602pmid:21791556
    OpenUrlCrossRefPubMedWeb of Science
    1. Pfannenberg C,
    2. Werner MK,
    3. Ripkens S, et al
    . Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 2010;59:1789–1793pmid:20357363
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Lee P,
    2. Greenfield JR,
    3. Ho KK,
    4. Fulham MJ
    . A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2010;299:E601–E606pmid:20606075
    OpenUrlAbstract/FREE Full Text
    1. Jacene HA,
    2. Cohade CC,
    3. Zhang Z,
    4. Wahl RL
    . The relationship between patients' serum glucose levels and metabolically active brown adipose tissue detected by PET/CT. Mol Imaging Biol 2011;13:1278–1283
    OpenUrlCrossRefPubMed
  40. ↵
    1. Zingaretti MC,
    2. Crosta F,
    3. Vitali A, et al
    . The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009;23:3113–3120pmid:19417078
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Sharp LZ,
    2. Shinoda K,
    3. Ohno H, et al
    . Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 2012;7:e49452pmid:23166672
    OpenUrlCrossRefPubMed
  42. ↵
    1. Wu J,
    2. Boström P,
    3. Sparks LM, et al
    . Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150:366–376pmid:22796012
    OpenUrlCrossRefPubMedWeb of Science
  43. ↵
    1. Blondin DP,
    2. Labbé SM,
    3. Tingelstad HC, et al
    . Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metab 2014;99:E438–E446pmid:24423363
    OpenUrlPubMed
  44. ↵
    1. Yoneshiro T,
    2. Aita S,
    3. Matsushita M, et al
    . Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013;123:3404–3408pmid:23867622
    OpenUrlCrossRefPubMedWeb of Science
  45. ↵
    1. Betz MJ,
    2. Slawik M,
    3. Lidell ME, et al
    . Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature. J Clin Endocrinol Metab 2013;98:4097–4104pmid:23744406
    OpenUrlCrossRefPubMed
  46. ↵
    1. Lidell ME,
    2. Betz MJ,
    3. Dahlqvist Leinhard O, et al
    . Evidence for two types of brown adipose tissue in humans. Nat Med 2013;19:631–634pmid:23603813
    OpenUrlCrossRefPubMed
  47. ↵
    1. Cypess AM,
    2. White AP,
    3. Vernochet C, et al
    . Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 2013;19:635–639pmid:23603815
    OpenUrlCrossRefPubMed
  48. ↵
    1. Jespersen NZ,
    2. Larsen TJ,
    3. Peijs L, et al
    . A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab 2013;17:798–805pmid:23663743
    OpenUrlCrossRefPubMedWeb of Science
  49. ↵
    1. Rao RR,
    2. Long JZ,
    3. White JP, et al
    . Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014;157:1279–1291pmid:24906147
    OpenUrlCrossRefPubMedWeb of Science
  50. ↵
    1. Qiu Y,
    2. Nguyen KD,
    3. Odegaard JI, et al
    . Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 2014;157:1292–1308pmid:24906148
    OpenUrlCrossRefPubMedWeb of Science
  51. ↵
    1. Schulz TJ,
    2. Huang TL,
    3. Tran TT, et al
    . Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci USA 2011;108:143–148pmid:21173238
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Silva FJ,
    2. Holt DJ,
    3. Vargas V, et al
    . Metabolically active human brown adipose tissue derived stem cells. Stem Cells 2014;32:572–581pmid:24420906
    OpenUrlCrossRefPubMed
  53. ↵
    1. Russell AP,
    2. Crisan M,
    3. Léger B, et al
    . Brown adipocyte progenitor population is modified in obese and diabetic skeletal muscle. Int J Obes (Lond) 2012;36:155–158pmid:21522126
    OpenUrlCrossRefPubMed
  54. ↵
    1. Vijgen GH,
    2. Bouvy ND,
    3. Teule GJ,
    4. Brans B,
    5. Schrauwen P,
    6. van Marken Lichtenbelt WD
    . Brown adipose tissue in morbidly obese subjects. PLoS One 2011;6:e17247pmid:21390318
    OpenUrlCrossRefPubMed
  55. ↵
    1. Vijgen GH,
    2. Bouvy ND,
    3. Teule GJ, et al
    . Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab 2012;97:E1229–E1233pmid:22535970
    OpenUrlCrossRefPubMedWeb of Science
  56. ↵
    1. Kopecky J,
    2. Clarke G,
    3. Enerbäck S,
    4. Spiegelman B,
    5. Kozak LP
    . Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest 1995;96:2914–2923pmid:8675663
    OpenUrlCrossRefPubMedWeb of Science
  57. ↵
    1. Cederberg A,
    2. Grønning LM,
    3. Ahrén B,
    4. Taskén K,
    5. Carlsson P,
    6. Enerbäck S
    . FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 2001;106:563–573pmid:11551504
    OpenUrlCrossRefPubMedWeb of Science
  58. ↵
    1. Kim JK,
    2. Kim HJ,
    3. Park SY, et al
    . Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance. Diabetes 2005;54:1657–1663pmid:15919786
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Collins S,
    2. Daniel KW,
    3. Petro AE,
    4. Surwit RS
    . Strain-specific response to β 3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology 1997;138:405–413pmid:8977430
    OpenUrlCrossRefPubMedWeb of Science
  60. ↵
    1. Collins S,
    2. Daniel KW,
    3. Rohlfs EM,
    4. Ramkumar V,
    5. Taylor IL,
    6. Gettys TW
    . Impaired expression and functional activity of the beta 3- and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice. Mol Endocrinol 1994;8:518–527pmid:7914350
    OpenUrlCrossRefPubMedWeb of Science
  61. ↵
    1. Yoneshiro T,
    2. Ogawa T,
    3. Okamoto N, et al
    . Impact of UCP1 and β3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans. Int J Obes (Lond) 2013;37:993–998pmid:23032405
    OpenUrlCrossRefPubMed
  62. ↵
    1. Nakayama K,
    2. Miyashita H,
    3. Yanagisawa Y,
    4. Iwamoto S
    . Seasonal effects of UCP1 gene polymorphism on visceral fat accumulation in Japanese adults. PLoS One 2013;8:e74720pmid:24086366
    OpenUrlCrossRefPubMed
  63. ↵
    1. Orava J,
    2. Nuutila P,
    3. Lidell ME, et al
    . Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011;14:272–279pmid:21803297
    OpenUrlCrossRefPubMedWeb of Science
  64. ↵
    1. Chondronikola M,
    2. Volpi E,
    3. Børsheim E, et al
    . Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014;63:4089–4099pmid:25056438
    OpenUrlAbstract/FREE Full Text
  65. ↵
    1. Orava J,
    2. Nuutila P,
    3. Noponen T, et al
    . Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring) 2013;21:2279–2287pmid:23554353
    OpenUrlCrossRefPubMed
  66. ↵
    1. Lee P,
    2. Smith S,
    3. Linderman J, et al
    . Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 2014;63:3686–3698pmid:24954193
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Bartelt A,
    2. Bruns OT,
    3. Reimer R, et al
    . Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011;17:200–205pmid:21258337
    OpenUrlCrossRefPubMedWeb of Science
  68. ↵
    1. Geerling JJ,
    2. Boon MR,
    3. van der Zon GC, et al
    . Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes 2014;63:880–891pmid:24270984
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. Ghorbani M,
    2. Himms-Hagen J
    . Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats. Int J Obes Relat Metab Disord 1997;21:465–475pmid:9192230
    OpenUrlCrossRefPubMedWeb of Science
  70. ↵
    1. Umekawa T,
    2. Yoshida T,
    3. Sakane N,
    4. Saito M,
    5. Kumamoto K,
    6. Kondo M
    . Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. Eur J Endocrinol 1997;136:429–437
    OpenUrlAbstract/FREE Full Text
  71. ↵
    1. Weyer C,
    2. Tataranni PA,
    3. Snitker S,
    4. Danforth E Jr.,
    5. Ravussin E
    . Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans. Diabetes 1998;47:1555–1561pmid:9753292
    OpenUrlAbstract
  72. ↵
    1. van Baak MA,
    2. Hul GB,
    3. Toubro S, et al
    . Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther 2002;71:272–279pmid:11956510
    OpenUrlCrossRefPubMedWeb of Science
  73. ↵
    1. Larsen TM,
    2. Toubro S,
    3. van Baak MA, et al
    . Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr 2002;76:780–788pmid:12324291
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Cypess AM,
    2. Weiner LS,
    3. Roberts-Toler C, et al
    . Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 2015;21:33–38pmid:25565203
    OpenUrlCrossRefPubMed
  75. ↵
    1. Carey AL,
    2. Formosa MF,
    3. Van Every B, et al
    . Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia 2013;56:147–155pmid:23064293
    OpenUrlCrossRefPubMedWeb of Science
  76. ↵
    1. Cypess AM,
    2. Chen YC,
    3. Sze C, et al
    . Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci USA 2012;109:10001–10005pmid:22665804
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. Carey AL,
    2. Pajtak R,
    3. Formosa MF, et al
    . Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity. Diabetologia 2015;58:1045–1054
    OpenUrlCrossRefPubMed
  78. ↵
    1. Lahesmaa M,
    2. Orava J,
    3. Schalin-Jäntti C, et al
    . Hyperthyroidism increases brown fat metabolism in humans. J Clin Endocrinol Metab 2014;99:E28–E35pmid:24152690
    OpenUrlCrossRefPubMed
  79. ↵
    1. Amorim BS,
    2. Ueta CB,
    3. Freitas BC, et al
    . A TRbeta-selective agonist confers resistance to diet-induced obesity. J Endocrinol 2009;203:291–299pmid:19713219
    OpenUrlAbstract/FREE Full Text
  80. ↵
    1. Villicev CM,
    2. Freitas FR,
    3. Aoki MS, et al
    . Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol 2007;193:21–29pmid:17400799
    OpenUrlAbstract/FREE Full Text
  81. ↵
    1. Watanabe M,
    2. Morimoto K,
    3. Houten SM, et al
    . Bile acid binding resin improves metabolic control through the induction of energy expenditure. PLoS One 2012;7:e38286pmid:22952571
    OpenUrlCrossRefPubMed
  82. ↵
    1. Watanabe M,
    2. Houten SM,
    3. Mataki C, et al
    . Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484–489pmid:16400329
    OpenUrlCrossRefPubMedWeb of Science
  83. ↵
    1. Boström P,
    2. Wu J,
    3. Jedrychowski MP, et al
    . A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463–468pmid:22237023
    OpenUrlCrossRefPubMedWeb of Science
  84. ↵
    1. Elsen M,
    2. Raschke S,
    3. Eckel J
    . Browning of white fat: does irisin play a role in humans? J Endocrinol 2014;222:R25–R38pmid:24781257
    OpenUrlAbstract/FREE Full Text
  85. ↵
    1. Lee P,
    2. Linderman JD,
    3. Smith S, et al
    . Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014;19:302–309pmid:24506871
    OpenUrlCrossRefPubMedWeb of Science
  86. ↵
    1. Zhang Y,
    2. Li R,
    3. Meng Y, et al
    . Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 2014;63:514–525pmid:24150604
    OpenUrlAbstract/FREE Full Text
  87. ↵
    1. Roberts LD,
    2. Boström P,
    3. O’Sullivan JF, et al
    . β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 2014;19:96–108pmid:24411942
    OpenUrlCrossRefPubMedWeb of Science
  88. ↵
    1. Tseng YH,
    2. Kokkotou E,
    3. Schulz TJ, et al
    . New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008;454:1000–1004pmid:18719589
    OpenUrlCrossRefPubMedWeb of Science
    1. Boon MR,
    2. van den Berg SA,
    3. Wang Y, et al
    . BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One 2013;8:e74083pmid:24066098
    OpenUrlCrossRefPubMed
  89. ↵
    1. Whittle AJ,
    2. Carobbio S,
    3. Martins L, et al
    . BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 2012;149:871–885pmid:22579288
    OpenUrlCrossRefPubMedWeb of Science
  90. ↵
    1. Hondares E,
    2. Iglesias R,
    3. Giralt A, et al
    . Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011;286:12983–12990pmid:21317437
    OpenUrlAbstract/FREE Full Text
  91. ↵
    1. Moisan A,
    2. Lee YK,
    3. Zhang JD, et al
    . White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol 2015;17:57–67pmid:25487280
    OpenUrlPubMed
  92. ↵
    1. Chen KY,
    2. Brychta RJ,
    3. Linderman JD, et al
    . Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J Clin Endocrinol Metab 2013;98:E1218–E1223pmid:23780370
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top
Diabetes: 64 (7)

In this Issue

July 2015, 64(7)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Human Brown Adipose Tissue: What We Have Learned So Far
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Human Brown Adipose Tissue: What We Have Learned So Far
Matthias J. Betz, Sven Enerbäck
Diabetes Jul 2015, 64 (7) 2352-2360; DOI: 10.2337/db15-0146

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Human Brown Adipose Tissue: What We Have Learned So Far
Matthias J. Betz, Sven Enerbäck
Diabetes Jul 2015, 64 (7) 2352-2360; DOI: 10.2337/db15-0146
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Origins of BAT and Two Types of BAT
    • (Re)discovery of BAT in Human Adults
    • The Role of BAT in Insulin Resistance and Obesity Diabetes in Humans
    • BAT as a Potential Drug Target To Treat Obesity and Diabetes in Humans
    • Article Information
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations
  • Brown and Beige Fat: Molecular Parts of a Thermogenic Machine
Show more Diabetes Symposium: Browning of Adipose Tissue—What's New?

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.