Review Article

Metabolic syndrome and related conditions

pISSN: 2287-4208 / eISSN: 2287-4690
World J Mens Health Published online Jan 19, 2023
https://doi.org/10.5534/wjmh.220224

Thermogenic Brown Fat in Humans: Implications

in Energy Homeostasis, Obesity and Metabolic
Disorders
Masayuki Saito , Yuko Okamatsu-Ogura
Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan

In mammals including humans, there are two types of adipose tissue, white and brown adipose tissues (BATs). White adipose
tissue is the primary site of energy storage, while BAT is a specialized tissue for non-shivering thermogenesis to dissipate en-
ergy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active
BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. It is now established
that BAT, through its thermogenic and energy dissipating activities, plays a role in the regulation of body temperature, whole-
body energy expenditure, and body fatness. Moreover, increasing evidence has demonstrated that BAT secretes various para-
crine and endocrine factors, which influence other peripheral tissues and control systemic metabolic homeostasis, suggesting
BAT as a metabolic regulator, other than for thermogenesis. In fact, clinical studies have revealed an association of BAT not
only with metabolic disorders such as insulin resistance, diabetes, dyslipidemia, and fatty liver, but also with cardiovascular
diseases including hypertension and atherosclerosis. Thus, BAT is an intriguing tissue combating obesity and related metabol-
ic diseases. In this review, we summarize current knowledge on human BAT, focusing its patho-physiological roles in energy
homeostasis, obesity and related metabolic disorders. The effects of aging and sex on BAT are also discussed.

Keywords: Aging; Brown adipose tissue; Energy expenditure; Metabolic syndrome; Obesity; Sex

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial 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.

INTRODUCTION of triglyceride (TG) in adipose tissues because of a pro-

We have been facing a worldwide pandemic of obe-
sity, which is closely associated with not only muscu-
loskeletal disorders but also common diseases such as
diabetes mellitus, dyslipidemias, fatty liver, hyperten-
sion, and arteriosclerosis. Moreover, obesity predisposes
to adverse outcomes in some diseases, as in the ex-
ample of the increased mortality in patients with CO-
VID-19. Obesity is the state of excessive accumulation
longed positive energy balance. In mammals including
humans, there are two types of adipose tissue, white
and brown adipose tissues (BATs). The two tissues are
similar in their major population of adipocyte having
intracellular lipid droplets, but are quite different in
the physiological functions. White adipose tissue (WAT)
is the primary site of energy storage, while BAT is
a specialized tissue for non-shivering thermogenesis
(NST) to dissipate energy as heat.

Received: Oct 12, 2022 Accepted: Nov 8, 2022 Published online Jan 19, 2023
Correspondence to: Masayuki Saito https://orcid.org/0000-0002-3058-3003
Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Kita-ku, Kita18 Nishi-9, Sapporo 060-0818, Japan.
Tel: +81-11-706-5205, Fax: +81-11-757-0703, E-mail: saito@vetmed.hokudai.ac.jp

Copyright © 2023 Korean Society for Sexual Medicine and Andrology

 https://doi.org/10.5534/wjmh.220224

Although BAT research has long been limited mostly BAT-dependent CIT, together with skeletal muscle
in small rodents, the rediscovery of metabolically active shivering, plays a role in the maintenance of body
BAT using fluorodeoxyglucose (FDG)-positron emission temperature under cold conditions. In fact, BAT ther-
tomography (PET) and computed tomography (CT) in mogenesis is activated by acute cold exposure, and mice
adult humans [1-4] has dramatically accelerated the deficient of uncoupling protein 1 (UCP1), a key mito-
translational studies on BAT in health and diseases. It chondrial molecule for BAT thermogenesis, are cold-in-
is now established that BAT, through its thermogenic tolerant and cannot maintain their body temperature
and energy dissipating activities, plays a role in the after acute cold exposure [10,11]. Similarly, in humans,
regulation of body temperature, energy expenditure cold exposure activates BAT as reflected as increased
(EE), and body fatness [5,6]. Moreover, over a past de- uptake of FDG and fatty acid derivatives on PET im-
cade, increasing evidence has demonstrated that BAT aging (Fig. 1A) [1,2,4,12-16]. Moreover, the cold-induced
cross talks with some peripheral tissues and controls metabolic activation of BAT correlates positively with
their functions, systemic homeostasis of energy and CIT (Fig. 1B, 1C) [12,17,18], confirming a significant role
metabolic substrates, suggesting BAT as a metabolic of BAT for CIT in humans. Now, cold-induced FDG up-
regulator beyond thermogenesis [7-9]. In this review, we take is used as a surrogate of activity and amount of
summarize current knowledge on human BAT, with BAT in humans.
reference to its patho-physiological roles in energy ho- EE above the basal metabolic rate in response to
meostasis, obesity and metabolic diseases. meal intake is referred to as the “specific dynamic ac-
tion of food” or “diet-induced thermogenesis (DIT)”,
BROWN FAT AS A SITE OF ENERGY which is another component of NST [19,20]. As men-
EXPENDITURE BY NON-SHIVERING tioned above, cold exposure is the most potent and
THERMOGENESIS physiological stimulus to activate BAT, but BAT-de-
pendent CIT would be very low in our daily life under
In general, daily energy consumption is roughly di- well-controlled conditions with the presence of clothing
vided into three components: basal/resting EE, exercise/ and heating systems. In contrast, DIT is observed after
physical activity-associated EE, and NST. A represen- every meal intake independently of environmental
tative example of NST is cold-induced thermogenesis temperature, and estimated as about 10% of ingested
(CIT), an increased EE seen after cold exposure. It is energy of food. DIT is usually divided into two compo-
now well-established that BAT is a site of CIT, and nents: obligatory and facultative thermogenesis. Oblig-

A 18
F-FDG-PET/CT

BAT-negative BAT-positive
Fig. 1. Brown adipose tissue (BAT), en-
ergy expenditure (EE), and non-shivering
B C D
Basal EE CIT DIT thermogenesis. (A) BAT detected by 18F-
Energy expenditure (kcal/d)

Energy expenditure (kcal/d)

Energy expenditure (kcal/d)

1,600 800 ** FDG-PET/CT after acute cold exposure.

300 15 *
(B) Basal EE under a warm condition.
1,500 600 (C) Cold-induced thermogenesis (CIT)
200 10 after acute cold exposure. (D) Diet-
%

1,400 400
induced thermogenesis (DIT) after meal
100 5 intake. *p<0.05, **p<0.01. Adapted
1,300 200
from Yoneshiro et al (Obeisty [Silver
Spring] 2011;19:13-6) [12] and con-
0 0 0 0
+ + + structed from Hibi et al (Int J Obes [Lond]
BAT BAT BAT 2016;40:1655-61) [29].

2 www.wjmh.org
 Masayuki Saito and Yuko Okamatsu-Ogura: Thermogenic Brown Fat in Humans
atory thermogenesis refers to the obligatory response
including digestion, absorption, and storage of ingested
nutrients, whereas facultative thermogenesis refers to
the additional responses to obligatory thermogenesis
and may be closely related to BAT activation. Activa-
tion of BAT after food intake has been proved in small
rodents. For example, a single meal ingestion produced
a rapid increase in tissue respiration [21], glucose uti-
lization and fatty acid synthesis in intact BAT of rats,
but to a much lower extent in surgically denervated
BAT [22]. Moreover, EE after food intake is lower in
UCP1-deficient mice than in wild-type mice [23]
In humans, the possible contribution of BAT thermo-
genesis to DIT was suggested by Nagai et al [24], who
showed that single nucleotide polymorphism (SNP) in
the UCP1 gene is associated with reduced DIT. Redis-
covery of BAT in adult humans has prompted further
studies to test whether BAT thermogenesis is activated
after single meals. Some studies using FDG-PET/CT re-
vealed a reduced or unexpectedly low FDG uptake into
BAT after meal intake [25,26]. Although these results
seem conflicting with the idea of postprandial activa-
tion of BAT thermogenesis, they can be explained by
increased insulin-stimulated FDG uptake into skeletal
muscle, which reduces FDG bioavailability for BAT,
which in turn leads to underestimation of BAT activ-
ity [26].
This limitation of FDG-PET/CT is overcome by mea-
suring oxygen uptake using 15O[O2]-PET and blood flow
using 15O[H2O]-PET, which are direct indicators of ther-
Diet-induced
thermogenesis
Glossopharyngeal/
facial N
Taste
receptors
Food
Sympathetic N
Vagus N
NA
AR
CCK
Secretin SCTR
Bile acids TGR5 UCP1
Brown/beige
adipocyte
mogenesis and mitochondrial substrate oxidation [27].
Din et al [28] demonstrated that oxygen consumption
and blood flow in BAT rose immediately after meal
intake to an extent comparable to those observed after
cold exposure. To confirm the role of BAT in DIT, we
measured whole-body EE continuously for 24 hours
in healthy humans using a human calorimeter [29,30].
When the participants were divided into BAT-positive
and -negative groups according to the result of FDG-
PET/CT examination, there was no significant differ-
ence in body composition and basal EE between the
two groups. However, EE after meals was significantly
higher in the BAT-positive group (9.7% of the total
energy intake) than in the BAT-negative group (6.5%)
(Fig. 1D), suggesting that about 3% is BAT-dependent.
All these results indicate that BAT contributes to DIT,
at least in part, in humans.
MECHANISMS OF BROWN-FAT
ASSOCIATED NON-SHIVERING
THERMOGENESIS
The mechanism of cold-induced activation of BAT
has extensively been investigated in vivo and in vitro,
and is schematically depicted in Fig. 2. When animals
are exposed to cold temperatures, cold is perceived by
temperature sensors, transient receptor potential (TRP)
channels, which are membrane proteins that transmit
information about changes in the environment such as
temperature, touch, pain, osmolarity, and naturally oc-
Cold-induced
thermogenesis
Somato-
sensory N
TRP
Cold
Fig. 2. Neuro-endocrine mechanisms of
cold- and diet-induced brown fat ther-
mogenesis. βAR: β-adrenergic receptor,
CCK: cholecystokinin, SCTR: secretin
receptor, N: nerve, NA: noradrenaline,
TGR5: G-protein-coupled bile acid-
activated receptor, TRP: transient recep-
Heat tor potential channel, UCP1: uncoupling
protein 1.
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 https://doi.org/10.5534/wjmh.220224
curring substances. Cold-activated TRP on sensory neu-
rons on the body surface transmit information to the
brain and increase the activity of sympathetic nerves
(SNs). Noradrenaline (NA) released from SN endings
stimulates brown adipocytes via the β-adrenergic recep-
tor (βAR) and triggers intracellular events including
hydrolysis of TG, oxidation of resulting fatty acids, and
activates UCP1.
When animals are exposed to cold temperatures for a
long time, they adapt to their surroundings by increas-
ing the number of brown adipocytes and the amount of
UCP1 through the proliferation of interstitial preadi-
pocytes and matured adipocytes [31,32]. In addition to
BAT hyperplasia, prolonged cold exposure gives rise to
an apparent induction of UCP1-positive adipocytes in
WAT. This type of adipocytes, termed “beige” or “brite”
cells, is developmentally distinct from “classical” brown
adipocytes [33,34], and has the thermogenic potential in
response to βAR stimulation [35,36]. Thus, chronic cold
exposure results in increased EE through the persis-
tent activation and recruitment of classical brown adi-
pocytes and beige cells, and the consequent “browning”
of WAT and body fat reduction. As the UCP1-positive
human adipose depot consists of a mixture of brown
and beige adipocytes [37-39], here we refer to it collec-
tively as BAT and thermogenic adipocytes.
Several mechanisms/factors have been proposed to
participate in postprandial BAT activation. Based on
the principal role of the SN-βAR axis for CIT, it is con-
ceivable that this axis is also a key mechanism in BAT-
associated DIT (Fig. 2). In fact, in both experimental
animals and humans, the plasma levels of NA and tis-
sue NA turnover are low during fasting but increases
immediately after food intake [40-43]. We [22] found in
rats that postprandial metabolic activation of BAT was
diminished either after surgical severing of SNs enter-
ing BAT or by giving a meal through a gastric tube.
LeBlanc et al [40] and Diamond et al [44] showed in
humans and dogs that responses in oxygen consump-
tion, and plasma levels of NA and insulin shortly after
food intake were substantially reduced when food was
administered through a stomach tube. These results
collectively suggest a significant role of sympathetic
activation triggered by oropharyngeal taste sensation
in BAT-associated DIT.
Food intake evokes a rapid release of various gas-
trointestinal hormones, some of which are likely fac-
tors participating in DIT. Li et al [45] found abundant
4 www.wjmh.org
expression of the secretin receptor in murine brown
adipocytes, and demonstrated that secretin activates
UCP1- and secretin receptor-dependent thermogenesis
in vitro and in vivo. They also confirmed in humans
that the increment of plasma secretin levels induced
by a single meal positively correlated with BAT activ-
ity, and that secretin infusion increased FDG uptake
in BAT. In addition to secretin, other gut hormones
such as cholecystokinin and glucagon-like peptide 1
were suggested to triggers BAT thermogenesis in small
rodents through the vagal afferent and sympathetic
nervous system [46,47]. A stimulatory role of the va-
gal afferent in BAT thermogenesis was also reported
in humans [48]. Another humoral factor may be bile
acids, which are secreted into the intestinal lumen in
response to meal intake and modified by gut flora. Bile
acids are now recognized as a metabolic regulator, af-
fecting multiple functions, in addition to lipid-digestive
functions, to regulate energy metabolism, as well as
glucose and lipid metabolism [49]. In fact, bile acids
were reported to activate BAT thermogenesis in mice
and humans [50-52]. Thus, it is conceivable that these
multiple gut derived factors, together with the SN
system, participate in BAT-associated DIT, but further
studies are needed to uncover the detailed neuroendo-
crine mechanisms of DIT in humans.
BROWN FAT AS A REGULATOR OF
ENERGY BALANCE AND BODY FAT
Consistent with the significant role of BAT in NST
and short-term regulation of EE, there is substantial
evidence for BAT as a long-term regulator of EE and
body fatness: almost all obese model animals express
lower levels of UCP1 in BAT, while mice over-express-
ing UCP1 are leaner [53,54]. Mice lacking UCP1 get
obese when they are kept at thermoneutral tempera-
tures [55] or on a high-fat diet [56].
In humans, studies on SNP in some BAT-related
genes have suggested a significant contribution of
BAT thermogenesis to regulation of energy balance
and body fatness. For example, Trp64Arg mutation
in the β3AR gene and A3826G mutation in the UCP1
gene are associated with higher body fat content, lower
metabolic rate, and smaller weight loss via treatment
with low-calorie diets [57-60]. Consistently, retrospective
readings of FDG-PET/CT in thousands of patients have
revealed that BAT prevalence is lower in patients with
 Masayuki Saito and Yuko Okamatsu-Ogura: Thermogenic Brown Fat in Humans

higher BMI [3,61-64]. Prospective studies in healthy also been reported in various clinical studies [3,61,62].
participants also demonstrated that BAT-negative sub- The aging process produces increased fat mass and
jects are higher in their adiposity-related parameters decreased lean mass, therefore, it is possible that age-
than BAT-positive subjects (Fig. 3A) [1,2,65-67]. Thus, related accumulation of body fat is associated with de-
the inverse relationship between BAT and body fat- creased BAT activity. This is supported by the findings
ness is well confirmed (Fig. 3B). The apparent associa- that the adiposity-related parameters increased with
tion between BAT prevalence and adiposity, however, age in the BAT-negative group, while they remained
is to be carefully evaluated, because these are consider- unchanged from the twenties to forties in the BAT-
ably influenced by age. In fact, the mean age is lower positive group (Fig. 3D) [67]. BAT-associated NST is
in the BAT-positive participant group than the BAT- rather small (<100 kcal/day) in our daily life (Fig. 1C,
negative group (Fig. 3A). Detailed analysis revealed 1D), but it is maximally 36,500 kcal/year, equivalent to
that the prevalence of cold-activated BAT is more than 4 kg fat, which may be enough to explain the age-relat-
50% in young subjects of the twenties, decreased with ed accumulation of body fat. Such age-related changes
age, and in less than 10% of the fifties and sixties (Fig. in BAT will be discussed again in a latter section.
3C) [67]. A strong impact of age on BAT prevalence has

A Age (y) Age (y) B

40 20 0 0 20 40
Male Female
Age 100

Visceral fat (cm )

2
BMI 80

Total fat
60

Visceral fat BAT+

BAT
40
200 150 100 50 0 0 50 100 150 200 -0.5 0 0.5 1.0 1.5
2 2
Fat area (cm ) Fat area (cm ) BAT activity (relative)

C D E
Baby Young Old
60 120 * Energy
100 expenditure
BAT prevalence (%)

Visceral fat (cm )

Visceral fat (cm )

BAT
2

Lean
40
75 80

Inactivation Reactivation
20 of BAT of BAT
50 40 BAT+
2

Energy Obese
expenditure
0 25 0
20 30 40 50 >60 20 30 >40
29 39 49 59 29 39
Age (y) Age (y)
Fig. 3. Age-related changes in brown fat and body fatness. The prevalence and activity of brown adipose tissue (BAT) was assessed by FDG-PET/
CT combined with acute cold exposure. (A) Mean age and obesity-related parameters in subjects with detectable BAT (BAT+) and those without it
(BAT-). (B) Inverse correlation between BAT activity and visceral fat area. (C) Effects of age on BAT prevalence and visceral fat area. (D) Age-related
accumulation of visceral fat in subjects with detectable BAT (BAT+) and those without it (BAT-). (E) The thermogenic activity of BAT is high during
neonatal periods, but decreases with age in some individuals who get obese. In contrast, other individuals who keep BAT during their adulthood
do not get obese, suggesting that BAT is protective against age-related accumulation of body fat, and that its reactivation/recruitment is effective
for combating obesity. *p<0.05, **p<0.01. Constructed from Saito et al (Diabetes 2009;58:1526-31) [1] and Yoneshiro et al (Obesity [Silver Spring]
2011;19:1755-60) [67].

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 https://doi.org/10.5534/wjmh.220224

ACTIVATION AND RECRUITMENT OF man BAT, it would seem difficult to increase exposure
BROWN FAT AS AN ANTI-OBESITY to cold in daily life. As shown in Fig. 2, cold stimulus
REGIMEN is received by TRP. Among the members of the TRP
family, TRPM8 and TRPA1 are the most likely recep-
The finding that BAT is protective against body fat tor candidates sensitive to low temperatures [74]. The
accumulation has encouraged the search how to acti- mean activation temperatures of TRPA1 and TRPM8
vate or recruit BAT (Fig. 3E). This is particularly in- are around 20°C, being comparable with those ap-
triguing because people with lower or undetectable BAT plied in human studies to activate BAT. Accordingly,
activities are more obese and to be treated. As noted chemical activation of these receptors would mimic
in previous sections, cold is the most physiological and the effects of cold exposure. Actually, there are various
powerful stimulus for activation and recruitment of ingredients in food acting as agonists for these TRPs
BAT. Cold exposure elicits increased proliferation and [74], a representative of which is menthol, a cooling and
differentiation of classical brown adipocyte but also flavor compound in mint, acting on TRPM8. TRPA1 is
a remarkable induction of beige adipocytes in WAT. activated by allyl- and benzyl-isothiocyanates, pungent
Some genes expressed selectively in mouse beige cells elements in mustard and Wasabi (Japanese horserad-
are also highly expressed in human supraclavicular fat ish). Among the TRP agonists, the most extensively
deposits identified as BAT by FDG-PET/CT [37,68,69]. studied is capsaicin, a pungent principle of chili pep-
Lee et al [70] reported that preadipocytes isolated from per, which is a potent agonist for a nociceptive receptor
human supraclavicular fat were capable of differenti- TRPV1. Both animal and human studies have dem-
ating into UCP1-positive adipocytes in vitro. Moreover, onstrated that capsaicin and its nonpungent analogue
we found that BAT activity in humans is remarkably (capsinoids) increase BAT thermogenesis through the
increased during winter in individuals who showed activation of TRPV1 and the SN system, and decrease
undetectable activities in summer [1]. All these facts body fat [71,75-78]. Thus, these food ingredients activat-
suggest that human BAT is largely composed of beige ing TRPs may be promising as an anti-obesity regimen
cells and inducible in response to appropriate stimula- easily applicable in daily life [79,80].
tion. In fact, when men with undetectable or low BAT Pharmacological activation of BAT thermogenesis
activity were kept in a cold environment for 2–6 hours targeting β3AR expressed abundantly in adipocytes has
every day for several weeks, their BAT activity was long been expected as an anti-obesity regimen, while the
significantly increased while body fat was decreased β3AR agonists so fat developed showed, more or less,
[71-73] (Fig. 4A, 4B). More importantly, the change in undesirable cardiovascular side effects in humans [81,82].
BAT activity was negatively correlated with those in Among them, mirabegron may be promising, because it
body fat content [71] (Fig. 4C). These results indicate induces WAT browning with minimal side effects. Clini-
that human BAT can be induced and/or recruited, and cally, mirabegron is widely used for the treatment of
is involved in reducing body fat. overactive bladder, because it relaxes the smooth muscle
Although daily cold exposure thus can recruit hu- of the bladder where β3AR is expressed [83]. Cypess et

A B C
6 0.4 3.0
*
2.0 R= 0.703
0.0 Fig. 4. Recruitment of brown fat and
BAT activity (SUV)

p=0.023
1.0 reduction of body fat by repeated cold
Body fat (kg)

Body fat (kg)

4
0.4 0.0 exposure. Participants were exposed to
either a cold (Cold) or warm (Control)
1.0
0.8 condition for 2 hours every day for 6
2
2.0 weeks. (A) Brown adipose tissue (BAT)
1.2 activity assessed by FDG-PET/CT. (B)
3.0
* Changes in body fat. (C) Correlation be-
0 1.6 4.0 tween the changes in body fat and BAT
0 6 Cold Control 2 0 2 4 6 activity. Adapted from Yoneshiro et al (J
Cold exposure (wk) BAT (SUV) Clin Invest 2013;123:3404-8) [71].

6 www.wjmh.org
 Masayuki Saito and Yuko Okamatsu-Ogura: Thermogenic Brown Fat in Humans

al [84] reported acute mirabegron treatment increases
FDG uptake into BAT, in parallel with an increase in
EE, heart rate, and blood pressure, at a high dose (200
mg/kg), but only slightly at clinically approved doses (50
mg/kg). Following studies, however, demonstrated that
chronic treatment with 50 mg/kg mirabegron induces
UCP1 in WAT and improved glucose homeostasis [85-87].
It is to be noted in these studies that chronic mirabe-
gron treatment resulted in undetectable change in body
fatness, but improved glucose tolerance and insulin sen-
sitivity, suggesting beneficial effects of beige adipocytes
on systemic metabolism as discussed in the next section.
BROWN FAT REGULATES
SYSTEMIC METABOLISM BEYOND
THERMOGENESIS
Increasing evidence has suggest that BAT has an
impact on systemic metabolism, independent of that
on the regulation of EE and body fatness. For instance,
mouse studies have shown that transplantation of
BAT or brown adipocytes results in improved glucose
tolerance and increased insulin sensitivity [88,89]. In
humans, we [66] found in healthy adults that blood
glucose and HbA1c levels are lower in individuals with
higher BAT activities, BAT being an independent
determinant of these parameters (Fig. 5A). These re-
sults seem compatible with retrospective analyses of
patient data showing blood glucose as a determinant
of BAT prevalence [3,62-64]. Chondronikola et al [90]
reported that mild cold exposure increased whole-body
glucose disposal, plasma glucose oxidation, and insulin
sensitivity in men with significant amounts of BAT,
but not in those without detectable BAT. Improved
insulin sensitivity in parallel with BAT recruitment
after cold acclimation was also shown in healthy men
[91,92] and in patients with type 2 diabetes mellitus
[93]. In connection with the beneficial effects of BAT
on insulin sensitivity, interesting is that BAT actively
metabolizes branched chain amino acids (BCAA) to
lower their plasma levels in humans [94]. Since the ac-
cumulation of intracellular BCAA is known to inhibit
insulin signaling through mTOR activation, impaired
insulin sensitivity often seen in obesity and aging may
be attributable to increased circulating BCAA result-
ing from reduced BAT activity [95].
Very recently, Seki et al [96] reported that the BAT-
associated changes in systemic glucose metabolism re-
sult in a marked suppression of tumor. Exposure of tu-
mor-bearing mice to cold conditions inhibits the growth

A B

Glucose T2DM

HbA1c Dyslipidemia

Insulin AF

HOMA-R CAD

HDL-Cho CVD

LDL-Cho CHF

TG Hypertension

0.5 1.0 1.5 2.0 0.5 1.0 1.5

Odds ratio Odds ratio
Fig. 5. Impact of brown fat on blood parameter and cardiometabolic diseases. (A) Blood parameters in healthy subjects. HDL-Cho: high-density
lipoprotein cholesterol, LDL-Cho: low-density lipoprotein cholesterol, TG: triglyceride. Constructed from Matsushita et al (Int J Obes [Lond]
2014;38:812-7) [66]. (B) Cardiometabolic diseases. AF: atrial fibrillation/atrial flutter, CAD: coronary artery disease, CHF: congestive heart failure,
CVD: cerebrovascular disease, T2DM: type 2 diabetes. Closed circles show a significant association with BAT independent of body adiposity, age,
and sex. Adapted from Becher et al (Nat Med 2021;27:58-65) [64].

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 https://doi.org/10.5534/wjmh.220224
of various types of solid tumor. The cold-induced tumor
suppression is ablated by surgical removal of BAT and
feeding on a high-glucose diet, and in UCP1-deficient
mice. Mechanistically, cold-induced BAT activation
results in increased systemic glucose metabolism and
decreased blood glucose, which impedes the glycolysis-
based metabolism in cancer cells. A pilot study in a
patient with Hodgkin’s lymphoma showed a markedly
reduced FDG uptake into the tumor tissue after mild
cold exposure, but more human studies are needed to
strengthen its clinical relevance.
BAT has also significant effects on systemic lipid
metabolism. The main energy source of BAT thermo-
genesis is fatty acids derived from intracellular TG
and incorporated from circulation. BAT activation by
cold exposure markedly accelerates clearance of plasma
TG-rich lipoproteins due to increased uptake into BAT,
and corrects hyperlipidemia [97]. Similar effects were
also found by pharmacologic activation of BAT with a
ß3AR agonist, which improves dyslipidemia, and more
importantly, protects hyperlipidemic model mice from
atherosclerosis [98]. Activation of BAT thermogenesis
increases high-density lipoprotein (HDL) levels, pro-
moting HDL cholesterol turnover [86,99]. All these facts
suggest a direct contribution of BAT to the regulation
of blood lipoprotein metabolism.
The effects of BAT on systemic metabolism would be
closely related to the etiology of various metabolic and
Fatty acid uptake
Exercise capacity
12,13-diHOME
Muscle Myostatin
Lipogenesis NRG4
Fgf21 Exosomal
expression miR-99b
IL-6
Inflammation Maresin 2
Stress-induced Insulin sensitivity
gluconeogenesis
Liver
8 www.wjmh.org
cardiovascular diseases [100]. Becher et al [64] catego-
rized 53,475 patients by presence or absence of BAT,
and found improved profiles of blood glucose, TG, and
HDL-cholesterol in individuals with BAT, as already
reported in healthy humans. Notably, BAT indepen-
dently correlated with lower rates of type 2 diabetes,
dyslipidemia, hypertension, coronary artery disease,
and congestive heart failure (Fig. 5B). These results are
well consistent with previously reported association
between BAT and diabetes [62] and also with a 5-year
follow-up study [101] showing that BAT activity cor-
related with lower carotid intima-media thickness and
higher carotid elasticity. An association of BAT with
hepatic steatosis was also reported in humans [102-104].
BROWN FAT-DERIVED ENDOCRINE
FACTORS AFFECTING SYSTEMIC
METABOLISM
As mentioned above, even small amounts of BAT
influence the broad range of systemic metabolisms.
Mechanistically, some of the effects may be attrib-
uted to the relatively high metabolic activity of BAT
itself, as in the case of the lowering effect on TG-rich
lipoprotein and BCAA; however, other effects seem dif-
ficult to be explained solely by its own activity. In this
connection, it is interesting that BAT secretes various
molecules into extracellular fluid, collectively called as
Thermogenesis
Sympathetic
nerve growth
NGF Brown fat
VEGF Angiogenesis
Beige adipocyte
FGF21 induction
Fig. 6. Endocrine actions of brown
fat-derived factors, BATkines: 12,13-
diHOME,12,13-dihydroxyoctadecaenoic
Energy expenditure
acid, FA: fatty acid, FGF21: fibroblast
growth factor 21, IL-6: interleukin-6, miR:
Whole body microRNA, NGF: nerve growth factor,
NRG: neuregulin 4, VEGF: vascular endo-
thelial growth factor.
 Masayuki Saito and Yuko Okamatsu-Ogura: Thermogenic Brown Fat in Humans
batokine (BATkine), which may mediate the effects of
BAT on other tissues [8,105] (Fig. 6).
Activated BAT secretes some growth factors, such as
vascular endothelial growth factor and nerve growth
factors, which promote angiogenesis and SN growth
associated with tissue hyperplasia [106-108]. In addition
to these paracrine factors, BAT secretes a wide variety
of polypeptides into circulating blood. Among them,
interleukin-6 (IL-6) may be a likely BATkine to regu-
late systemic glucose metabolism. In the study of BAT
transplantation, Stanford et al [109] found that the im-
proved metabolic profile was lost when the BAT used
for transplantation was obtained from IL-6-deficient
mice. Qing et al [110] reported that acute stress induces
IL-6 secretion from BAT, which is the required instruc-
tive signal for mediating hyperglycemia through he-
patic gluconeogenesis.
Another candidate of BATkines is fibroblast growth
factor 21 (FGF21). FGF21 is released abundantly from
the liver, but it is also released from activated BAT
and contributes to increased circulating levels [111-113].
FGF21 is known as an important regulator of systemic
metabolism and whole-body energy balance; it increas-
es energy expenditure by inducing BAT thermogenesis
and WAT browning, while it suppresses sugar intake
by actin on the ventromedial hypothalamus. FGF21
stimulates glucose utilization in WAT, hepatic fatty
acid oxidation, and peripheral lipoprotein catabolism
[114,115]. Ruan et al also [116] reported that brown
adipocyte-specific FGF21 knockout impaired the effects
of adenosine A2A receptor agonism in attenuating
hypertensive cardiac remodeling, suggesting an endo-
crine role of BAT in controlling hypertensive cardiac
remodeling though the release of FGF21. Despite many
studies in mice, however, it remains to be investigated
whether FGF21 secreted from BAT, compared with
that from the liver, plays key physiological roles in hu-
mans.
In addition, many polypeptides such as neureglin4
(NRG4) and myostatin were identified as BATkines
[117,118], but a comprehensive overview is beyond the
scope of this article and found in other literatures
[8,105].
MicroRNAs (miRNAs) may serve as signals between
BAT and other tissues. miRNAs produced in adipo-
cytes have a role in the differentiation and function of
adipocyte itself and are also secreted through exosomes
and taken-up into other cells [119]. Thomou et al [120]
reported that mice with adipose-tissue-specific deletion
of the miRNA-processing enzyme exhibit a substantial
decrease in the levels of circulating exosomal miRNAs,
including miRNA-99b, and that the transplantation of
BAT restores the circulating miRNA level, improves
glucose tolerance, and suppresses hepatic FGF21 ex-
pression. These results suggest that exosomal miRNA-
99b is secreted from BAT into blood circulation, acts
on the liver, and suppresses hepatic FGF21 expression.
It was also reported that circulating levels of miR-92a-
3p and miRNA-122 are inversely correlated with BAT
activity in humans [121,122].
Some lipid molecules are also suggested as active
BATkines. Oxylipins, molecules derived from the oxi-
dation of polyunsaturated fatty acids, are attracted in-
terest because of their action as intercellular signaling
molecules and involvement in the regulation of many
cell and tissue responses. Particularly interesting is a
linoleic acid derivative 12,13-dihydroxyoctadecaenoic
acid (12,13-diHOME) secreted from BAT upon cold ex-
posure. 12,13-diHOME activates BAT in autocrine man-
ner to enhance thermogenesis, resulting in decreased
levels of serum TGs [123]. Moreover, 12,13-diHOME
secretion from BAT is enhanced by exercise and in-
creases fatty acid uptake in muscle [124]. Very recently,
Sugimoto et al [125] reported that cold- and β3AR ag-
onist-activated BAT produces maresin 2, a member of
the anti-inflammatory pro-resolving mediators synthe-
sized from docosahexaenoic acid, and reduces inflam-
mation in obesity in part by targeting macrophages in
the liver. A role of BAT metabolism of succinate, an
intermediate of the tricarboxylic cycle, has also been
suggested in liver inflammation. Cold exposure produc-
es substantial and selective accumulation of succinate
in BAT, which is sufficient to elevate UCP1-dependent
thermogenesis and sequester elevated circulating succi-
nate [126,127]. In contrast, without UCP1, BAT exhibits
a diminished capacity to clear succinate from the cir-
culation, and elevated extracellular succinate in liver
tissue that drives inflammation through the action on
liver resident stellate cells and macrophages [128]. As
such, BAT may regulate liver immune cell infiltration
and pathology through succinate metabolism.
In addition, several small molecules were identified
as BATkine candidates: for example, 3-methyl-2-oxova-
leric acid, 5-oxoproline and β-hydroxyisobutyric acid
synthesized in and released from brown adipocytes
induce thermogenic gene expression in white adipo-
www.wjmh.org 9
 https://doi.org/10.5534/wjmh.220224
cytes and energy metabolism in skeletal myocytes [129].
Thus, BATkines are likely to mediate the beneficial
effects of activated BAT on other tissues/organs, but
their pathophysiological roles in humans are largely
elusive to date.
AGE-RELATED CHANGES IN BROWN
FAT FUNCTIONS
As mentioned above, BAT is a promising tissue
combating obesity and cardiometabolic diseases. It is
also true, however, that the amount and activity of
human BAT decline remarkably with age, while the
prevalence of these diseases increases. Accordingly, it
is important to understand the mechanisms/factors of
age-related decline of BAT and how to re-activate and
recruit BAT in elderly [130].
Ageing is associated with a decline of both classical
and beige adipocytes, reflected by increased intracel-
lular lipid accumulation, reduced mitochondrial and
UCP1 content, and reduced ability of beige adipocyte
induction [131,132]. There is a heterogenous population
of beige adipocyte progenitor cell, which is maintained
during postnatal life by its ability to proliferate and
differentiate in response to beiging signals [133]. Aging
is associated with not only an impaired ability of beige
adipocyte progenitor cell to proliferate, which leads to
a marked decrease in the progenitor cell number, but
also a decreased differentiating ability of the progeni-
tor cell [134-136].
The age-related change of BAT is regulated by mul-
tiple intrinsic factors, including a longevity gene Sir-
tuin 1 [137], CD81 [138], and the FSTL1 gene encoding
the follistatin-like one glycoprotein [139]. Mitochondrial
dysfunctions are also likely to link intrinsically to age-
related decline of BAT thermogenic function [140]. Ta-
jima et al [141] reported that mitochondrial lipoylation
is reduced in aged BAT, but its enhancement by a-
lipoic acid supplementation restores BAT function,
thereby preventing age-associated obesity and glucose
intolerance.
Among various neuro-endocrine mechanisms/factors,
the SN- bAR system may be critical. In aged animals,
sympathetic signaling to BAT is greater both at ther-
moneutrality and during cold exposure [142,143], where-
as BAT cell proliferation induced by cold exposure is
substantially attenuated [144]. These facts imply that
ageing is associated with the decreased sensitivity of
10 www.wjmh.org
BAT to sympathetic stimulation. Consistent with this
idea, there is a report demonstrating decreased β3AR
mRNA expression and impaired cellular responses to
adrenergic stimulation in BAT of aged mice [145]. This
seems well compatible with the observations in hu-
mans that SN activity increases with age, while ther-
mogenic response to cold decreases [146]. We demon-
strated a significant impact of SNP in the β3AR gene
on the age-related decline in human BAT [60]. Bahler
et al [147] reported, however, using imaging technics
with a 123I-labelled NA analogue and 18F-FDG, that both
sympathetic drive and BAT activity are lower in older
men than in younger men. Thus, further studies are
needed to draw out the precise mechanism underlying
the age-related decline in BAT in terms of SN activity.
Another likely mechanism is related to the produc-
tion of pro-inflammatory mediators by macrophages
infiltrating in adipose tissue [148]. It is known that the
number of M1, but not M2 macrophage, in adipose tis-
sue increases in obesity. While anti-inflammatory resi-
dent M2 macrophages are stimulatory to beige adipo-
cyte induction [149], pro-inflammatory M1 macrophages
impair brown adipocyte activity and beige adipogenesis
[150-152]. Pro-inflammatory cytokines such as tumor
necrosis factor a and interleukin-1β induce a decreased
viability of brown adipocytes accompanied by a mas-
sive reactive oxygen species production and down-
regulation of thermogenic gene expression [153], and
induce apoptosis of brown adipocytes [154]. It is thus
likely that increased infiltration of M1 macrophage
in WAT facilitates the attenuated browning of WAT,
suggesting the suppression of M1 macrophage activity
in WAT would be effective to induce beige adipocytes,
thereby preventing against obesity and related meta-
bolic disorders.
SEX DIFFERENCES IN BROWN FAT
Ageing is associated with several endocrine changes,
including diminished gonadal function. Animal stud-
ies have demonstrated sex differences in BAT: for ex-
ample, compared to BAT of male rats, that of females
shows higher mitochondrial density and cristae height,
higher UCP1 levels, and higher sensitivity to adrener-
gic stimulation [155]. Higher ability of WAT browning
was also reported in female mice [156]. A comprehen-
sive gene expression analysis revealed higher UCP1
expression in WAT of female mice [157]. Consistently,
 Masayuki Saito and Yuko Okamatsu-Ogura: Thermogenic Brown Fat in Humans
human studies have demonstrated sex difference in
CIT and BAT throughout the life span [158,159]. In
children, the activity and mass of BAT change slightly
with age along with sexual maturation, being higher in
prepubertal girls than in boys [160]. In adults, although
the prevalence of BAT detected by FDG-PET scans
markedly declines with age, its sex difference persists,
being higher in women than in men [3,61-63,161,162].
Moreover, higher UCP1 expression and browning po-
tential of WAT in women were reported [163,164]. It is
to be careful, however, that the sex difference in BAT
detected by FDG-PET may not always reflect the dif-
ference in the amount and/or intrinsic activity of BAT.
In almost all clinical studies in patients so far reported,
FDG-PET was carried out at room temperatures with-
out maximizing BAT activity by cold exposure. Con-
sidering sexual dimorphism of thermic, metabolic and
cardiovascular responses to cold exposure [165], as well
as cold sensation [166], it is possible that the above-
mentioned sex difference in human BAT may be due
to the difference in the sensitivity to cold stimulus. In
fact, several prospective studies in healthy participants
revealed no significant sex difference in the prevalence
and activity of BAT estimated under cold conditions
[15,167,168], despite of higher CIT in women.
The sex dimorphism suggests the direct and indirect
effects of gonadal hormones on BAT [169]. Estrogens
are the most likely hormone to enhance the activity
and differentiation of BAT [170]. The stimulatory ef-
fects of estrogens are mediated both directly through
the action on nuclear receptors (ER) expressed in
brown adipocytes [171] and indirectly through the
brain-SN system [172]. In contrast to estrogens, andro-
gens were reported to inhibit differentiation and UCP1
expression in brown adipocytes in vitro [173,174]. In
vivo studies reported that surgical removal of testis re-
sults in increased UCP1 expression in BAT and WAT
[175,176]. These results seem consistent with those in
human studies that hyperandrogenism in women as
in polycystic ovary syndrome (PCOS) is associated
with lower BAT activity and obesity [177,178]. Reduced
UCP1 expression was also found in androgen-induced
PCOS model animals [179,180]. However, in vivo ef-
fects of androgens so far reported are controversial.
For example, several studies have shown no effects of
dihydroxytestosterone treatment on UCP1 expression
in BAT of orchiectomized mice or female mice [181-
183]. Moreover, mice deficient of the nuclear androgen
receptor were shown to display a reduced expression of
thermogenic genes in BAT and get obese [184]. Thus,
the in vivo effects of androgens appear rather compli-
cated, but a part of them may be explained by locally
increased estrogen level due to intratissue aromatizai-
tion of androgens in WAT and the brain [185]. In fact,
the testosterone-induced reduction of WAT mass in
hypogonadal male mice requires ER in the brain [186].
Further studies are needed to uncover the mechanisms
and factors responsible to the sex differences in BAT.
CONCLUSION AND FUTURE
PERSPECTIVES
As discussed throughout the previous sections, BAT
participates in the regulation of whole-body EE, sys-
temic metabolism, and cardiovascular functions in
humans. Accordingly, this specific tissue is now rec-
ognized as an intriguing therapeutic target of obesity
and metabolic disorders such as diabetes mellitus,
dyslipidemia, and related cardiovascular diseases. In
fact, several drugs and food ingredients targeting BAT
have been tested for pharmacological and nutritional
therapy of obesity and metabolic syndrome [79,81,187].
Although not discussed in this article, possible contri-
bution of BAT to some beneficial effects of exercise is
also suggested, particularly in context with the inter-
action between skeletal muscle and beige adipocytes
[188,189].
Despite these advances in BAT researches, there are
some unsolved but critical problems in humans, includ-
ing the genetic and environmental factors responsible
for a remarkable individual difference in the amount
and activity of BAT, and the patho-physiological rel-
evance of UCP1-independent thermogenic mechanisms
of beige adipocytes [190]. Particularly important is the
method used in assessing human BAT. To date, FDG-
PET is a standard tool [191]; however, this method has
serious limitations, including the enormous cost of
devices, radiation exposure, and acute cold exposure,
which make repeated measurements difficult and an
impediment in basic and clinical studies. Moreover, the
uptake of FDG into BAT is not always associated with
its thermogenic activity. There is therefore an urgent
need to establish less invasive and simpler methods for
quantitative assessment of human BAT [192-195]. This
would promote prospective human studies, including
longitudinal observations and the development of prac-
www.wjmh.org 11
 https://doi.org/10.5534/wjmh.220224
tical, easy, and effective regimens that can activate
and recruit BAT.
Conflict of Interest
The authors have nothing to disclose.
Funding
None.
Author contribution
Writing-original draft: MS, Writing-review & editing: YOO.
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