The Journal of Physiology - 2023 - Zhu - Adipose Tissue Browning and Thermogenesis Under Physiologically Energetic

J Physiol 602.
1 (2024) pp 23–48 23
TOPICAL REVIEW
Adipose tissue browning and thermogenesis under

physiologically energetic challenges: a remodelled
thermogenic system
Yupeng Zhu1,2,3 , Weina Liu1,2 and Zhengtang Qi1,2
1
The Key Laboratory of Adolescent Health Assessment and Exercise Intervention (Ministry of Education), East China Normal University, Shanghai,
China
2
School of Physical Education and Health, East China Normal University, Shanghai, China
3
Sino-French Joint Research Center of Sport Science, East China Normal University, Shanghai, China
Handling Editors: Laura Bennet & Jean-Claude Béïque

The Journal of Physiology
The peer review history is available in the Supporting Information section of this article
(https://doi.org/10.1113/JP285269#support-information-section).
Abstract Metabolic diseases such as obesity and diabetes are often thought to be caused by
reduced energy expenditure, which poses a serious threat to human health. Cold exposure,
exercise and caloric restriction have been shown to promote adipose tissue browning and thermo-
genesis. These physiological interventions increase energy expenditure and thus have emerged as
promising strategies for mitigating metabolic disorders. However, that increased adipose tissue
browning and thermogenesis elevate thermogenic consumption is not a reasonable explanation
when humans and animals confront energetic challenges imposed by these interventions. In this
review, we collected numerous results on adipose tissue browning and whitening and evaluated
this bi-directional conversion of adipocytes from the perspective of energy homeostasis. Here, we
propose a new interpretation of the role of adipose tissue browning under energetic challenges:
increased adipose tissue browning and thermogenesis under energy challenge is not to enhance
energy expenditure, but to reestablish a more economical thermogenic pattern to maintain the
core body temperature. This can be achieved by enhancing the contribution of non-shivering
thermogenesis (adipose tissue browning and thermogenesis) and lowering shivering thermo-
genesis and high intensity shivering. Consequently, the proportion of heat production in fat
© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society. DOI: 10.1113/JP285269
14697793, 2024, 1, Downloaded from https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP285269 by Libya Hinari NPL, Wiley Online Library on [18/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
24 Y. Zhu and others J Physiol 602.1
increases and that in skeletal muscle decreases, enabling skeletal muscle to devote more energy
reserves to overcoming environmental stress.
(Received 9 August 2023; accepted after revision 16 November 2023; first published online 29 November 2023)
Corresponding authors Z. Qi and W. Liu: School of Physical Education and Health, East China Normal University,
Shanghai 200241, China. Email: ztqi@tyxx.ecnu.edu.cn; wnliu@tyxx.ecnu.edu.cn
Abstract figure legend Physiological energetic challenges including cold stress, exercise and caloric restriction remodel
the thermogenic system of the organism, leading to an increased non-shivering thermogenesis in the adipose tissue and a
decreased shivering thermogenesis in the skeletal muscle. The remodelled thermogenic system improves the utilization
of fatty acids, which both elevates thermogenic endurance and conserves glucose, enabling the organism to maintain
body temperature in a more economical and sustainable manner during periods of energy deprivation. Created with
BioRender.com.
Introduction the browning of adipose tissue and activation of BAT

under energetic challenge are solely aimed at further
In comparison to ectotherms, which can adjust their body increasing overall energy expenditure, this may actually
temperature based on the surrounding environment, end- be detrimental for sustainable survival in these situations.
otherms maintain a core temperature of between 36°C and This paradox challenges the traditional viewpoint. Studies
38°C, a narrow range, to minimize the impact of external have shown that there are compensatory mechanisms in
temperature fluctuations on their bodies. However, response to energetic challenges (Careau et al., 2021; Hill
this process undoubtedly incurs a considerable energy et al., 1984). These mechanisms help maintain energy
cost (Else & Hulbert, 1981). Non-shivering thermo- balance by coordinating energy consumption across
genesis (NST) and shivering thermogenesis (ST) are various physiological activities, resulting in a remodelled
crucial pathways for endotherms to defend normal body energy consumption system. Therefore, we propose here
temperature. In recent years, the identification of brown an insight: increased browning and thermogenesis of
adipose tissue (BAT) and beige adipose tissue arising adipose tissue during energetic challenges may not aim
within white adipose tissue (WAT) in adult humans has to enhance overall energy output, but rather to establish
led to the revelation of their roles in regulating metabolism a more economical thermogenic pattern, which can be
and improving energy expenditure, establishing them as achieved by increasing the contribution of NST, while
the linchpin of energy homeostasis and metabolic health reducing ST and high intensity shivering. As a result,
(Cypess et al., 2009; Petrovic et al., 2010). Employing the proportion of heat production in fat increases while
non-pharmaceutical interventions, such as cold exposure, that in skeletal muscle decreases, which allows the body
exercise and caloric restriction, can stimulate the to allocate more energy reserves towards coping with
development of beige adipocytes and increase NST environmental stress.
(Jin et al., 2023; Picoli et al., 2020; Slocum et al., 2013). The review is intended to point out the limitation of the
However, these processes are highly energy-dependent. In traditional view in explaining adipose tissue browning and
order to adapt to high energy demands, animals develop thermogenesis under energetic challenges; to integrate
adaptive responses to either reduce energy expenditure or the results of bi-directional conversion (i.e. browning and
enhance energy absorption efficiency, or both, to increase whitening) of adipocytes from the perspective of energy
the odds of survival. For example, wading birds in the homeostasis; and finally to propose an understanding
high arctic have evolved larger intestines than those living about the thermogenic alterations that occur through
at lower altitude (Ruthrauff et al., 2015). Therefore, if energetic challenges.
0 After completing his undergraduate degree, Yupeng Zhu joined the lab of Dr Zhengtang Qi to pursue his interests in adipose
tissue biology with a particular focus on the metabolic effects of exercise on adipose tissue. He is currently completing the second
year of his master’s degree in the School of Physical Education and Health at East China Normal University. His future research
will focus on exploring the mechanism underlying adipose tissue thermogenesis and exercise-mediated energy metabolism.
© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.
J Physiol 602.1 Adipose tissue browning and thermogenesis 25
Energetic challenges and adipose tissue browning it regulates the levels of various immune factors including
interleukin (IL)-1β/4/6/10 (Goto et al., 2016; Knudsen
Energetic challenge refers to an increase in energy
et al., 2014; Li et al., 2017; Vargovic et al., 2018).
expenditure or a decrease in energy intake that creates
All these activities have been shown to influence the
an energy deficit, which reflects an imbalance between
browning and thermogenic programs. On the other hand,
energy availability and demand (Nilaweera & Speakman,
numerous cold-induced factors act on the above processes
2018; Touitou et al., 2021). We can list four energetic
in an independent or interactive manner (for detailed
challenges associated with adipose tissue browning and
discussions of these factors, see Peres et al., 2019; Silva,
thermogenesis: cold, exercise, caloric restriction, as well
2006). The extensive regulatory network of cold-induced
as cachexia as a more extreme pathological state.
adipose tissue browning and thermogenesis makes cold
one of the most effective interventions, and it is also
Cold. Endotherms upon encountering cold conditions one of the most studied. However, some existing issues
consume energy to avoid hypothermia and keep their should be noted, such as that differences in temperature
bodies operational. Cold is the best established method and cooling protocols (e.g. cold water immersion versus
of promoting adipose tissue browning and thermo- cold air exposure) may lead to different results (Golden
genesis, through extensive pathways. First, cold stimulates & Tipton, 1988; van der Lans et al., 2013), and there is
the sympathetic nervous system (SNS) to release also the question of how to distinguish long-term adaptive
noradrenaline (NA), which subsequently facilitates responses from short-term effects of stress. An example
BAT thermogenesis and the formation of beige adipose of the latter, Jankovic et al. (2015) indicated that a large
tissue within the innervated WAT (Jiang et al., 2023). number of thermogenic adipocytes were recruited at the
Three types of adrenergic receptors (β1AR, β2AR early stage of cold exposure, whereas only a few cells were
and β3AR) mediate the effects of the SNS on physio- able to maintain a beige phenotype after cold acclimation.
logical activities in adipose tissue. Genetic depletion of
these receptors has revealed their roles in regulating
adipose tissue browning and thermogenesis. For example, Exercise and physical activity. Physiological activities
β1-knockout (KO) mice exhibited hypothermia and a during exercise lead to energy consumption in which
blunted thermogenic response to NA and the β1 selective muscle activity can enhance the metabolic rate by 15–20
agonist dobutamine (Ueta et al., 2012). Interestingly, times. Long-term training further increases energy
β2-KO mice retained cold-induced thermogenesis due to expenditure during exercise (about 10%) (Berge et al.,
compensatory increases in the expression of the other two 2021). The close relationship between exercise and
receptors (Fernandes et al., 2014). While β3 adrenergic adipose tissue browning and thermogenesis has been
receptor agonists have been widely applied to stimulate detailed in a wide range of studies (Raun et al., 2020;
BAT thermogenesis and beige adipose tissue formation in Ringholm et al., 2013; Scheel et al., 2022). In addition
current studies (Cypess et al., 2015), a recent study under- to directly stimulating the SNS to initiate thermo-
scored that β2 signalling was the dominant pathway to genic and browning processes (Blondin et al., 2020;
modulate human BAT thermogenesis (Blondin et al., Scalzo et al., 2014), cytokines induced by exercise,
2020). Moreover, it should be noted that although β3-AR termed exerkines (Safdar et al., 2016), are involved
is involved in mediating cold-induced adipose tissue in remodelling and modulating the adipose tissue.
browning and thermogenesis, receptor agonists and cold Peroxisome proliferator-activated receptor γ coactivator
stress would drive distinct adipocyte populations to 1-α (PGC1α), a potent browning agent, mediates the
generate beige adipocytes through different pathways effects of exercise on a wide range of physiological
(Jiang et al., 2017). These integrated data suggest activities. A treadmill training for 5 weeks increased
contributions of the three adrenergic receptors to uncoupling protein 1 (UCP1) in epididymal WAT
cold-induced adipose tissue browning and thermogenesis. (eWAT) and inguinal WAT (iWAT) of wild-type mice,
However, contradictory conclusions and independent as while PGC1α knockout diminished shifts in thermo-
well as overlapping roles of the three receptors imply they genic gene expression (Ringholm et al., 2013). During
have intricate relationships. the differentiation of ear mesenchymal stem cells into
Apart from the activation of the SNS, cold also adipocytes, the absence of PGC1α expression led to
affects adipose tissue browning and thermogenesis by a failed transition into thermogenic beige adipocytes,
modulating the immune system. For example, cold instead favouring the formation of white adipocytes
regulates macrophage activity through stimulating the (Chu et al., 2022). The impact of PGC1α on adipose
expression of adiponectin (Hui et al., 2015) and CXCL5 tissue browning and thermogenesis also acts via the
(highly expressed in WAT macrophages) (Lee et al., 2021), interplay with other factors. Exercise-induced PGC1α
as well as other pathways (Cereijo et al., 2018; Keiran promoted the muscle to secrete fibronectin type III
et al., 2019; Suárez-Zamorano et al., 2015); alternatively, domain-containing protein 5 (FNDC5; which is cleaved
to irisin after maturation), and the resultant boost in irisin et al., 2014), long-term CR protects the browning capacity
levels subsequently enhanced UCP1 expression in WAT of WAT from age-related decline and promotes a healthy
and participated in other browning processes (Bostrom profile (Corrales et al., 2019; Fabbiano et al., 2016;
et al., 2012). Another study suggested that fibroblast Sheng et al., 2021). CR can be considered a milder
growth factor 21 (FGF21) functioned as an upstream energetic challenge compared to complete fasting, as it
activator to increase PGC1α levels in WAT, thereby more effectively maintains the balance between energy
stimulating the expression of UCP1 and other thermo- expenditure for thermogenesis and the need for energy
genic genes (Fisher et al., 2012). These data indicate storage, which consequently has a higher efficacy in
a profound requirement for PGC1α during adipose facilitating adipose tissue browning and thermogenesis.
tissue browning and thermogenesis in the context of Employing a new deconvolution algorithm to calculate
exercise. Additionally, small molecules (e.g. NO; Trevellin the brown adipocyte content in human and mouse
et al., 2014), FGF21 (Geng et al., 2019; Tanimura et al., biopsies, Perdikari et al. (2018) observed increased beige
2022), irisin (Zhang et al., 2014; Zhang, Xie, et al., 2016), adipocytes in patients receiving CR, as expected with the
brain-derived neurotrophic factor (Jodeiri et al., 2020; increased expression of the thermogenic markers UCP1
Sleiman et al., 2016), and lactate (Carrière et al., 2014) and Cidea. Consistent with the human results, 8 weeks of
have also been reported to act on adipose tissue browning CR rescued decreased thermogenic gene expression and
and thermogenesis. These factors, derived from various alleviated lipid accumulation in obese mice (Huang et al.,
parts of the body, reflect the active cross-talk across 2022). Furthermore, rats showed a correlated increase in
tissues and organs upon exercise, and provide potential BAT size following a long-term 40% CR intervention, but
therapeutic targets for related diseases. without a change in UCP1 levels (Selman et al., 2005).
However, the impacts of exercise on browning and This phenomenon may imply that saturated UCP1 levels
thermogenesis have been inconsistently reported (Knuth in BAT restrict the further development of thermogenic
et al., 2018; Martinez-Tellez et al., 2022; Singhal et al., function, which can only be achieved by cell proliferation
2016; Tsiloulis et al., 2018; Vosselman et al., 2015; Wu (Nedergaard et al., 2019). This raises the question of
et al., 2014). A consensus between animal and human whether there may be biological prioritization between
experimental results cannot yet be achieved. Differences two pathways that enhances thermogenic function
in intensity, duration and type of exercise may have led (promoting thermogenic adipocyte proliferation and
to divergent conclusions, leaving us without a unified thermogenic protein expression). Kalinovich et al. (2017)
understanding of the role of adipose tissue browning suggested that the expression and protein abundance of
and thermogenesis. As an advocated component of life- UCP1 would preferentially increase in thermoneutral
style, exercise plays a significant role in adipose tissue mice following browning stimuli. However, considering
browning and thermogenesis, which cannot be ignored. that BAT was completely differentiated at 21°C, expanding
Nevertheless, there is the question of whether elevated through proliferation might serve as the primary response
thermogenic parameters induced by exercise in humans to browning agents. Therefore, these regulatory pathways
imply only increased catabolic pathways, rather than seem to be affected to varying degrees in different physio-
thermogenic capacity (as catabolism and anabolism are logical settings, but how these processes are orchestrated
both active during exercise). Physical inactivity has always needs further elucidation.
been recognized as an important behavioural factor for On the other hand, dietary intervention has been
obesity and chronic diseases. Does exercise, as a reverse shown to offer superior metabolic benefits compared
behavioural intervention, have a reverse effect on adipose to pharmacological activation when it comes to
tissue browning and thermogenesis? Exercise is still a promoting adipose tissue browning and thermo-
promising intervention and may be more advantageous genesis. A week-long 26% CR improved mitochondrial
than cold stress because of its effects on modulating biogenesis and function-related gene expression (PGC1α,
adipose tissue plasticity and metabolism, as well as its TFAM, NRF1). Moreover, fatty acid metabolism and
pleiotropic health benefits (Khoo et al., 2015). transport-related genes were significantly upregulated,
which was not recapitulated in the group treated with
ephedrine (a sympathomimetic drug for increasing
Caloric restriction. Reducing energy intake (calorie energy expenditure and weight loss), suggesting that
restriction, CR) or periodically inducing nutrient scarcity CR activated additional nutrient sensing pathways to
in an organism (intermittent fasting, IF, or every other improve nutrient metabolism (Slocum et al., 2013). In
day fasting, EODF) is another promising approach light of these data, both short-term and long-term CR
to stimulate adipose browning and thermogenesis. In act on mediating adipose tissue browning and thermo-
contrast to a long-term fasting regimen, which impairs genesis. However, shifts in thermogenic gene mRNA
the activation of the SNS (Young & Landsberg, 1977) are immediate but transient (Nedergaard & Cannon,
and reduces BAT weight and thermogenic capacity 2013). Therefore, stable thermogenic protein levels may
(Nakamura et al., 2017; Shi et al., 2013; Syamsunarno be a more appropriate candidate to reflect the adaptive
response to CR. It is also noteworthy that there are colon cancer patients indicated that cancer cells induced
data suggesting an opposite role for CR in regulating WAT browning and lipolysis by releasing exosomes
adipose tissue browning (Barquissau et al., 2018; Yeganeh enriched in miR-146b-5p (Di W et al., 2021). Therefore,
et al., 2017). So, conflicting results present in essence a cancer-associated cachexia is always inseparable from
multifactorial outcome. The initial nutrient states (obese enhanced adipose tissue browning and thermogenic
or lean), the extent of CR and its duration – all these factors activity, allowing us to wonder whether cachexia causes
may contribute to the ultimately adaptive response. To our browning or browning aggravates cachexia. But all of
knowledge, current work has not conducted a systematic these processes are continuous and mutually reinforcing,
comparative analysis of the different protocols and results and it is difficult to disentangle causality.
of CR. Taking these factors into consideration may avoid In addition to cancer, cachexia triggered by CKD also
some misunderstandings and be beneficial in leveraging shows a significant increase in fat browning and thermo-
dietary intervention against obesity and other metabolic genesis. CKD mice showed increased resting energy
diseases. expenditure, UCP1 levels and citrate synthase in WAT,
indicating activated mitochondrial metabolism (Luce
et al., 2020). Treatment with vitamin D downregulated
Cachexia. Another extreme energetic challenge is browning markers and thermogenic gene expression,
cachexia under pathological conditions such as cancer as well as improving fat and lean body mass content
(Kir et al., 2014; Xie et al., 2022), burns, chronic kidney (Cheung, Ding, et al., 2020). Similarly, inhibiting IL-1
disease (CKD) (Cheung, Ding, et al., 2020; Cheung, levels reversed CKD-associated cachexia and reduced
Zheng, et al., 2021; Luce et al., 2020) and infantile adipose tissue browning (Cheung, Zheng, et al., 2021).
nephropathic cystinosis (Cheung et al., 2016; Cheung, Ctns−/− mice, an animal model for infantile nephrotic
Hao, et al., 2020; Cheung, Hao, et al., 2021). Although cystinosis, also show signs of increased adipose tissue
cachexia does not serve as an intervention imposing browning and hypermetabolism, along with a significant
energetic challenge, it is also characterized by hyper- loss of muscle mass. Cheung et al. (2016) unveiled the
metabolism, weight loss, muscle atrophy and enhanced expression of beige adipocyte markers CD137, TMEM26,
WAT browning (Baracos et al., 2018). Tbx1 and UCP1 in the iWAT of Ctns−/− mice, indicating
Here, we focus on the association between various an increase in browning in this model. Similar to
cancers and adipose browning and thermogenesis. CKD-associated cachexia, Ctns−/− mice treated with IL-1
A description of the mechanisms and treatment of antagonists for 6 weeks showed decreased browning
cancer-associated cachexia is beyond the scope of markers (Cheung, Hao, et al., 2021). Moreover, vitamin
this review but has been described in another elegant D supplementation also rescued adipose tissue browning
work (Abdullahi & Jeschke, 2017). Although a large and improved muscle fibre size and function via inhibiting
retrospective longitudinal cohort study of 8409 cancer muscle breakdown and promoting muscle regeneration
patients indicated that adipose tissue browning was (Cheung, Hao, et al., 2020).
independent of cancer-associated cachexia (Becker et al., Given the aforementioned results, adipose tissue
2020), and another study also highlighted that adipose browning has received particular attention among various
tissue browning was of little physiological relevance to physiological changes in cachexia, from which the
cachexia patients (Miller et al., 2020), more generally, robust correlation between high energetic challenges
however, a strong correlation between various types and browning stand out. But it is not clear whether
of cancer-associated cachexia and WAT browning has there is a significant difference between pathological
been observed. For example, in lung cancer models, and physiological adipose tissue browning and whether
tumour-derived parathyroid hormone-related protein the physiological significance under both conditions is
(PTHrP) drove increased thermogenic gene expression consistent. Further investigation regarding these problems
(UCP1, Dio2, PGC1α) and WAT browning, exacerbating should be conducted.
the development of cachexia (Kir et al., 2014). Exosomes
secreted by cells from Lewis lung carcinoma transported
Excess energy and adipose tissue whitening
extracellular PTHrP through fusion with adipocytes,
thus activating the intracellular protein kinase A (PKA) Adipose tissue whitening. While adipose tissue
pathway to induce WAT browning and lipolysis (Hu browning holds attractive promise as a treatment for
et al., 2021). Similarly, in the patients with pancreatic obesity and metabolic disorders, it is frustrating that beige
cancer, a dramatic increase in biomarkers of browning, adipocytes tend to lose their thermogenic characteristics
especially PGC1α expression, were observed in sub- and transition into a white phenotype when browning
cutaneous WAT (Molfino et al., 2022). Blocking the p38 stimuli are withdrawn (Altshuler-Keylin et al., 2016).
mitogen-activated protein kinase pathway alleviated It has been reported that at the early stage of cold
the browning phenotype and increased the volume and exposure, adipocytes in the retroperitoneal WAT would
mass of WAT (Zhao et al., 2022). Tissue samples from undergo transient thermogenic recruitment, upregulating
thermogenic gene expression and protein levels. After browning, the whitening process is dominated by
45 days of cold acclimation, however, thermogenic mitigation of energetic challenges, including a thermo-
proteins of most beige adipocytes returned to the baseline neutral environment (Cui et al., 2016; Kotzbeck et al.,
level, and only a few retained thermogenic characteristics 2018), excess energy intake (Lopez-Vicchi et al., 2022;
(Jankovic et al., 2015). The term ‘whitening’ describes Miranda et al., 2020) and physical inactivity (Nguyen
the transition from beige and brown phenotypes to et al., 2022; Takaishi et al., 2021). Ambient temperature
white adipocytes, which is the opposite physiological is a fundamental factor that directly determines heat
process to browning. The morphological characteristics production; thermoneutrality reduces the energy cost
of whitening include increased lipid droplets, decreased required for maintaining body temperature, thus
mitochondria content, and vascular rarefaction within alleviating energetic challenges. Roh et al. (2018) and
adipose tissue (Shimizu et al., 2014). At the molecular an earlier study (Rosenwald et al., 2013) suggested that
level, the expression of thermogenic proteins and genes cold-induced beige adipocytes transformed into white
is found to be impeded (Cui et al., 2016; Wei et al., adipocytes when the temperature was raised to thermo-
2020). Additionally, mitochondrial biogenesis and citrate neutrality (30°C). Interestingly, however, transformed
synthase activity are reduced, accompanied by a decrease adipocytes still retained ‘thermogenic memory’ and
in the abundance of proteins in the mitochondrial could respond and rapidly revert to the beige phenotype
respiratory chain or matrix (Cummins et al., 2014). The when stimulated by a new bout of cold. The memories
mechanism underlying adipose tissue whitening has of the cold were formed through modifications of the
been fully reviewed in another elegant work (Shimizu & epigenome, which preserved a series of enhancers of
Walsh, 2015) and due to limited space, we only discuss thermogenic genes during cold stimulation. In line
the influence of mitochondrial autophagy here. with this, a thermoneutral environment led to a trans-
Mitochondrial autophagy is considered a critical ition from the high-thermogenic brown adipocyte
factor driving the whitening process. Transcription factor subpopulation to a low-thermogenic subpopulation
EB (TFEB), a major regulator of lysosomal biogenesis (Song et al., 2020). Compared with the group living
and autophagy, promoted BAT whitening through under mild cold stress (21°C), striped hamsters upon
mitochondrial degradation, which was mediated by experiencing the thermoneutral condition significantly
autophagosomes and lysosomes. Whereas TFEB deletion downregulated COX activity and UCP1 expression in BAT,
preserved mitochondrial mass in BAT and primary with concomitant decrease in triiodothyronine/thyroxine
brown adipocytes (Sass et al., 2021), in mice fed a high-fat ratio in serum, which regulates thermogenic activity (Tan
diet (HFD), autophagosome- and autophagy-related et al., 2016). Employing nearly identical experimental
gene expression (Parkin and Pink1) were elevated, protocols, two studies demonstrated that thermo-
accompanied by a dramatic whitening in adipose tissue neutrality blunted exercise-induced adipose tissue
(Cummins et al., 2014). Moreover, specific knockout browning, which was evident from reduced thermo-
of Atg5 or Atg12 attenuated mitochondrial autophagy, genic and mitochondrial oxidative protein levels as well
which prevented the loss of the beige phenotype after as decreased energy expenditure (McKie et al., 2019;
withdrawing stimuli and sustained the high thermo- Raun et al., 2020). But there was a paradox regarding
genic capacity, so as to combat adipose tissue whitening other metabolic benefits induced by exercise. McKie et al.
(Altshuler-Keylin et al., 2016). This also fits with the (2019) believed that exercise influenced these benefits
data showing that Park2-ablated mice showed dampened regardless of temperature, whereas Raun et al. (2020)
mitochondrial degradation and were able to retain argued that thermoneutrality hindered these metabolic
thermogenic beige adipocytes after the external stimulus improvements. The discrepant results between the two
was removed. Treatment with NA was demonstrated to studies could be partly explained by the longer running
inhibit the recruitment of mitochondrial Parkin protein distances upon cold stress in the second experiment,
in beige adipocytes by activating the PKA pathway. This, which amplified the effect of ambient temperature on
in turn, hinders Parkin-mediated mitochondrial auto- metabolism.
phagy, thereby preventing whitening (Lu et al., 2018).
In light of these studies, mitochondrial autophagy plays
a crucial role in the whitening process of beige and Excess energy intake. As the largest energy reservoir in
brown adipose tissue by affecting multiple pathways. the body, adipose tissue maintains the balance between
Consequently, targeting or interfering with mitochondria energy consumption and storage. High energy intake is
degradation could be a potential approach to maintain the most common trigger of adipose tissue whitening.
the thermogenic capacity of adipocytes. A high-fat diet (HFD) led to WAT deposition and BAT
whitening in CD-1 mice, with enhanced inflammatory
Thermoneutrality. In contrast to the aforementioned factors and metabolic disorders (Gao et al., 2015).
high energetic challenges leading to adipose tissue HFD also decreased the number of nuclei and batokine
gene expression as well as thermogenesis in BAT, Adipocytes fate under energetic challenges
indicating an impaired thermogenic function and severe
Considering that high energetic challenges result in an
whitening (Rangel-Azevedo et al., 2022). Moreover, the
energy shortage for the organism, it does not appear to be
effects of high-caloric diets on whitening vary between
a prudent choice to further increase energy consumption
different nutrient components. Miranda et al. (2020)
as an adaptation to cope with such challenges. In fact,
suggested that although both high fructose and fat
this would be detrimental to organismal survival in
diets decreased glucose tolerance, only HFD led to
such situations. So how should we understand adipose
iBAT whitening, accompanied by lipid accumulation
tissue browning and thermogenesis in the context of
and decreased expression of thermogenic genes and
a great energy demand such as cold, exercise, caloric
β-oxidation. Treatment with PPARα-selective agonists
restriction and even cachexia? In view of previous studies,
ameliorated these metabolic disorders and enhanced
beige adipocytes may be a phenotype formed in low
thermogenic activity fuelled by fatty acids. However, their
nutrition or energy states, while adipocytes exist as the
recent work revealed that excess fructose intake could
white phenotype when energy is sufficient. This also
have a worse effect on BAT whitening and dysfunction
explains why lean individuals, who have lower energy
than HFD (Miranda et al., 2022). So the underlying
reserves than individuals with obesity, seem to possess
mechanism by which different nutrient components affect
a greater browning potential. An earlier study indicated
adipose tissue whitening may be a clue to uncovering the
that individuals with obesity had lower BAT mass and
disorder of substance metabolism, which may be related
activity (Vijgen et al., 2011). Thermogenic gene expression
to shifts in metabolic flexibility.
including UCP1, NRF1 and PGC1α was also decreased
compared with lean individuals (Huang et al., 2022).
Data from patients with morbid obesity suggested that
BAT activity was negatively correlated with obesity, and
functional BAT might be re-recruited after significant
Physical inactivity. Physical inactivity is also thought
weight loss (Vijgen et al., 2012). Moreover, obesity led
to promote fat whitening. In OLETF rats, childhood
to seriously attenuated sensitivity of BAT to cold and
exercise had an immediate inhibitory effect on BAT
insulin (Orava et al., 2013). Carey et al. (2013) reported
whitening and UCP1 downregulation induced by obesity.
that lean individuals (BMI, 22 ± 1 kg/m2 ) experienced
However, the inhibitory effect was diminished after
increased BAT activation when stimulated with high doses
detraining, and the density of unilocular white adipocytes
of ephedrine, but the same result was not recapitulated in
did not differ between the sedentary and exercise
the obese group (BMI, 36 ± 1 kg/m2 ). Another intriguing
group following 6 weeks of detraining (Takaishi et al.,
study revealed that participants with obesity reduced
2021). Similarly, detraining increased adipocyte size
branched-chain amino acid (BCAA) catabolism and the
and lipid accumulation, but exercise in early childhood
oxygenation of the adipose tissue (Cifarelli et al., 2020).
efficiently mitigated BAT whitening and decreased food
Given the crucial role of BCAA in fuelling adipose tissue
consumption until adulthood (Nguyen et al., 2022).
thermogenesis (Yoneshiro et al., 2019), decreased BCAA
In an earlier study, exercise rescued the regression of
concentrations and catabolism as well as oxygen partial
cold-induced NST irrespective of BAT thermogenesis,
pressure in adipose tissue may imply impaired NST in
implying that exercise might protect the thermogenic
humans with obesity. In animal experiments, obesity not
capacity of beige adipocytes and prevent their return
only impacted exercise-induced mitochondrial biogenesis
to white adipocytes (Moriya et al., 1988). These results
by hindering the expression of mitochondrial trans-
suggest a role of long-term exercise in maintaining
lation elongation factor-Tu (Greene et al., 2014), but
adipose tissue browning and thermogenic capacity, but the
attenuated the browning programme through down-
molecular mechanisms remain largely obscure stemming
regulating miR-27a, an upstream regulator of PPARγ
from limited data about the effects of exercise on adipose
(Wang et al., 2022). Obviously, as a natural insulating
tissue whitening.
material, fat is crucial for maintaining body temperature
Overall, loosening energetic constraints would drive
when animals are exposed to cold. Animals in polar
beige and brown adipocytes to return to a state of excess
regions are equipped with thicker fur and fat that endow
nutrition (i.e. white adipocytes). It can be seen that
with them a greater heat retention capacity and a wider
nutrient levels largely impact the phenotype of highly
range of thermoneutral zones, thereby decreasing the
plastic adipose tissue. We summarize the conclusions of
demand for thermogenesis (Scholander et al., 1950a,
adipose tissue browning and whitening under different
b). So it is not surprising that lean individuals with
energetic challenges in Table 1. In the following sections,
lower fat content are more susceptible to cold stress and
we gather relevant data to piece together a model that links
thus have higher browning potential and BAT activity.
browning and whitening of the adipose tissue based on
The relationship between fat content and NST is also
different nutrient levels.
Table 1. Adipose tissue browning and whitening in the context of energetic challenges
Ambient Protocols/pathological Adipose tissue browning or whitening

Types Species temperature conditions and muscle shivering
High energetic challenges

Cold Mice 23°C–25°C 6.5°C for 7 days UCP1+ beige adipocytes, PGC1α, Cidea
and UCP1 mRNA↑ (Jiang et al., 2017)
Mice 22°C 4°C for 3 days PGC1α and UCP1 mRNA↑ (Knudsen
et al., 2014)
Mice 22°C 6°C for 2 days UCP1, Prdm16, Cidea expression and
oxygen consumption↑ (Hui et al.,
2015)
Rats 24°C 4°C for 4 weeks Oxygen consumption and NST↑ but
shivering↓ (Moriya et al., 1988)
Humans 15–16°C for 10 days BAT activity and volume↑ NST↑ but no
(6 h/day) change in muscle NST, and
shivering↓(van der Lans et al., 2013)
Humans 14°C cold-water NST↑ but total shivering intensity
immersion for 7 days reduced by 36% (Gordon et al., 2019)
(1 h/day)
Humans 10°C for 4 weeks BAT volume and oxidative metabolism
(2 h/day) increase 45% and 182%, respectively.
But muscle NST and shivering↓
(Blondin, Daoud, et al., 2017)
Exercise Mice 22°C Wheel running for UCP1, mitochondrial proteins, oxygen
6 weeks consumption↑ but BAT weight↓
(Raun et al., 2020)
Mice Room A single treadmill UCP1 protein was unchanged after
temperature exercise bout and acute exercise but increased after
chronic training for chronic training, UCP1 mRNA↑ in
5 weeks both protocols (Ringholm et al., 2013)
Mice Room Swimming (30–35°C) for UCP1, PGC1α and TFAM mRNA↑
temperature 30 days (90 min daily, mitochondrial biogenesis↑ (Trevellin
5 days/week) et al., 2014)
Mice 25°C Wheel running for Core temperature at 4°C↑ unchanged
12 days NST in BAT but potentially increased
in muscle (Knuth et al., 2018)
Rats 23°C Treadmill running for UCP1, PGC1α and FNDC5 in WAT↑ but in
8 weeks (1 h daily, BAT↓ (Wu et al., 2014)
5 days/week)
Humans Female athletes BAT volume and activity↓ (Singhal et al.,
2016)
Humans Endurance exercise No change in browning markers (UCP1,
training for 6 weeks Tbx1, CD137) (Tsiloulis et al., 2018)
Humans Endurance and Unchanged BAT volume and glucose
resistance training for uptake (Martinez-Tellez et al., 2022)
24 weeks
Caloric Mice 23°C A daily intake of 800 Beige adipocyte content increased 9%,
restriction kcal for 12 weeks BAT content, UCP1 and Cidea mRNA↑
(Perdikari et al., 2018)
Mice Room 26% CR for 1 week PGC1α, TFAM, NRF1 and oxygen
temperature consumption↑ (Slocum et al., 2013)
Mice 24°C 30% CR for 8 weeks Adipocytes size, UCP1, UCP2, UCP3,
NRF1 and PGC1α↑(Huang et al., 2022)
Rats 24°C 40% CR for 22 months BAT mass↑ UCP1 levels unchanged
(Selman et al., 2005)
(Continued)
Table 1. (Continued)
Ambient Protocols/pathological Adipose tissue browning or whitening

Types Species temperature conditions and muscle shivering
Humans CR for 8 weeks (3.3–4.2 Browning markers (UCP1, PGC1α,

MJ/day) Elovl3)↓ (Barquissau et al., 2018)
Humans A daily intake of 800 UCP1,Cidea and COX7A1 expression↑
kcal (Perdikari et al., 2018)
Cachexia Cancer UCP1, Dio2, PGC1α↑ (Kir et al., 2014)
Cidea, PGC1α, Tmem26↑ UCP1↓ (Hu
et al., 2021)
Prdm16, UCP1, oxygen consumption↑
(Zhao et al., 2022)
Chronic kidney disease Prdm16, UCP1, PGC1α, Cidea and
resting energy expenditure↑ (Cheung,
Ding, et al., 2020)
Infantile nephrotic UCP1, UCP2, UCP3, PGC1α, Cidea and
cystinosis Dio2↑ ATP content↓ (Cheung, Hao,
et al., 2021)
Reduced energetic challenges
Thermo- Mice 22°C 4°C for 1 week then Unilocular adipocytes were induced.
neutrality 30°C for 8 weeks UCP1, Cox8b, Elovl6 and Cidea↓ (Roh
et al., 2018)
Mice 23°C 8°C for 1 week then UCP1, Cidea, Cox7a1, Tbx1↓ (Rosenwald
23°C for 5 weeks et al., 2013)
Mice 24°C 6°C for 1 week then UCP1, Cidea, Elovl6, OXPHOS,
30°C for 1 week mitochondrial membrane potential↓
(Song et al., 2020)
Mice 22°C 30°C for 6 weeks UCP1, mitochondrial proteins and
oxygen consumption↓ (Raun et al.,
2020)
Physical Rats 22 ± 2°C Detraining for 6 weeks Unilocular adipocytes↑, UCP1↓ (Takaishi
inactivity et al., 2021)
Rats 22 ± 2°C Detraining for 8 weeks Adipocytes size, lipid accumulation↑
(Nguyen et al., 2022)
Excess Mice 22°C High-fat diet for Number of nuclei↓ fat deposition,
energy 10 weeks whitening↑ (Gao et al., 2015)
intake
Mice 21 ± 2°C High-fat diet for 12, 16 BAT whitening↑ UCP1, NST, energy
and 20 weeks expenditure and batokines↓
(Rangel-Azevedo et al., 2022)
↑ parameters increase; ↓ parameters decrease. BAT, brown adipose tissue; NST, non-shivering thermogenesis; OXPHOS, oxidative
phosphorylation; WAT, white adipose tissue.
evidenced by the transformation of the NST capacity from According to the intensity of energetic challenges, we
birth to maturity in some mammals. For example, NST of divide the changes that may occur in adipocytes into
harp seal pups was largely involved in thermoregulation five zones, from low to high: a compensatory browning
during early development, whereas NST in BAT sustained zone, whitening zone, buffer zone, browning zone and
a progressive involution after weaning due to the maturity compensatory whitening zone. The external energetic
of blubber (Pearson et al., 2014). challenges alter the nutrient levels of adipocytes, and
Here, we propose a model to systematically illustrate shifts in phenotype occur when nutrient levels enter
the relationship between energetic challenges and adipose the corresponding zone. High energy expenditure
browning and whitening (Fig. 1). Energetic challenges transforms adipocytes into a low nutrition condition,
influence cellular nutrient levels, ultimately determining namely beige adipocytes, while excess energy intake and
whether adipocytes undergo whitening or browning. decreased energy expenditure enable the transformation
of adipocytes towards the white phenotype. Moreover, the whitening capacity after 24 h fasting, as evidenced
evidence suggests that adipocytes initiate compensatory by a decrease in Prdm16 expression and the number
browning and whitening under extreme conditions – of mitochondria and UCP1 positive adipocytes, with
energy surplus and energy scarcity, respectively. As concomitant larger lipid droplets, indicating that adipose
energetic challenges continue to increase and energy tissue compensated for maintaining energy reserves
reserves become depleted, thermogenic adipocytes will through attenuating its thermogenic function. Re-feeding
serve as energy stores. For example, 100 days of CR restored the reduced browning markers (Ding et al.,
resulted in a significant decrease in UCP1 content and 2016). Therefore, nutrient scarcity imposed by high
BAT weight in female rats (Valle et al., 2005). But this energetic constraints will force adipocytes to enter the
effect seemed to be sex-specific as males undergoing the compensatory whitening zone in an attempt to conserve
same CR regime as females exhibited no changes in BAT. more energy.
Striped hamsters under thermoneutrality also down- In stark contrast, the compensatory browning is
regulated UCP1 mRNA and BAT mass following an 80% associated with excess energy intake. HFD increased
CR intervention (Zhang, Zhao, et al., 2016). Of particular UCP1 and Cidea positive beige adipocytes in
interest, a change in function occurred between adipose retroperitoneal WAT in mice. Interestingly, these
tissue following 6 months of CR. Mitochondrial energy browning biomarkers returned to basic levels after ending
metabolism was elevated in WAT, but the expression of a HFD, suggesting a high sensitivity of beige adipocytes to
genes related to mitochondrial biogenesis and function energy intake levels (García-Ruiz et al., 2015). Moreover,
as well as thermogenesis was decreased in BAT, with both men and women with obesity exhibited a beige
concomitant increase in fatty acid synthesis, suggesting phenotype in the subcutaneous WAT, with women
that BAT might shift from an energy consumer to a showing a more pronounced effect (Barquissau et al.,
preserver (Okita et al., 2012). A similar phenomenon 2018). This observation could be attributed to the fact
was observed in another study. Adipocytes acquired that women generally have higher amounts of adipose
Figure 1. Energetic challenge intensity regulates adipose tissue browning and whitening
As caloric restriction, exercise, cold and cachexia enhance the intensity of energetic challenges, the nutrient levels
of organism gradually decrease, and adipocytes thus transition to a ‘low energy state’, namely beige adipocytes
(shifting to the right). But adipocytes initiate compensatory whitening to conserve energy when facing severe
nutrient scarcity. Factors including excess energy intake, physical inactivity and thermoneutrality mitigate energetic
challenges and thus increase nutrient levels and promote the development of adipocyte whitening (shifting to
the left). However, compensatory browning occurs to offset the accumulation of energy substrates when energy
reserves are in excess. Therefore, these two types of factors mediate the bi-directional conversion of adipocytes. If
the two diametrically opposed processes dampen mutually, which drives adipocytes to just enter the buffer zone
(‘?’ signifies that this zone is hypothetical), no obvious physiological change may occur. The lean individuals possess
higher browning potential than the obese due to their lower energy reserves. Created with BioRender.com.
tissue in their bodies, which may exemplify a strong higher metabolic efficiency and thermoneutrality) retard
association between browning capacity and fat content, the browning process to a higher extent in these contexts.
namely, energy reserve potential. However, CR eliminated This leads to a greater probability of entering the buffer
the browning characteristics, suggesting a potential shift zone, hence yielding many negative results (Aldiss et al.,
of adipocytes from the compensatory browning zone 2020; Barquissau et al., 2018; Martinez-Tellez et al., 2022;
to the buffer zone by depleting excess energy reserves. Scarpace et al., 1994; Tsiloulis et al., 2018).
Consequently, the adipocytes reverted back to their Another issue is that rodents are typically housed at
original white state. Additionally, glucocorticoid release, temperatures ranging from 22°C to 25°C, which is below
modulated by the hypothalamic–pituitary–adrenal their thermal neutral zone of 30°C (Ganeshan & Chawla,
axis, is a physiological response to energetic stressors 2017). This means that animals experience mild cold stress
and the subsequent decrease in energy availability. in these conditions. Consequently, when extrapolating
Excess glucocorticoids are considered to elicit metabolic the results of experiments conducted on animals to
disorders of BAT, and aggravate triglyceride accumulation humans, who naturally live within their thermal neutral
and whitening (Doig et al., 2017; Mousovich-Neto et al., zone, it is important to consider the potential influence
2019). In the work of Bel et al. (2022), treatment with of epigenetic-induced mechanisms. For example, under
corticosterone for 4 weeks exacerbated BAT whitening chronic cold stress, JMJD1A, a histone H3 lysine 9 (H3K9)
in mice, with increased body weight and adipocyte size. demethylase, promoted beige adipogenesis and thermo-
Nevertheless, increased BAT mass and UCP1 expression genic function in the subcutaneous WAT, through erasing
suggested that compensatory browning occurred in BAT H3K9me2 on the enhancer/promoter regions of thermo-
to offset excess lipid accumulation (Bel et al., 2022). genic genes and forming a PRDM16–PPARγ –p-JMJD1A
Therefore, the compensatory whitening and browning complex (Abe et al., 2018). Similarly, cold exposure
zones represent the elastic responses of the organism enhanced a ubiquitously transcribed tetratricopeptide
to high or low nutrient conditions, with the aim of repeat on chromosome X (UTX) in adipose tissue,
maintaining energy homeostasis. a histone demethylase for H3K27me2/3, which led
Most importantly, we propose a possible buffer zone to the activation of UCP1 and PGC1α promoters.
that connects the browning state with the whitening This activation occurred through the demethylation of
state and reflects the higher resistance of adipose tissue H3K27me3 and the acetylation of H3K27, resulting in a
to browning or whitening inducers, which may provide transcriptionally active state (Zha et al., 2015). Therefore,
an explanation for the negative results of adipose tissue it is reasonable that certain browning inducers may have
browning and thermogenesis under energetic challenges. lower effectiveness in humans, as animals are already
Individual differences in sensitivity to browning stimuli positioned closer to the browning zone and further away
and metabolic efficiency (i.e. the capacity absorbing and from the buffer zone prior to being subjected to various
consuming energy; Bouchard et al., 1990; Landsberg stimuli. Buffer zones are ubiquitous in living systems,
et al., 2009) may result in various effects on adipose such as the acid–base buffer system composed of various
tissue browning and thermogenesis, even when energetic ions, the energy buffer system composed of creatine
challenges are constantly imposed, such as leaving mice (phosphocreatine) and ATP (Kazak & Cohen, 2020) and
living in cold conditions. As mentioned above, on the many other cell pools, which reflects the elastic responses
assumption that nutrient levels are the fundamental of the body to resist external stress and maintain homeo-
determinant influencing adipocytes browning and stasis. We believe that the concept of the buffer zone
whitening, energy intake will act as a reversed driving in adipose tissue provides a feasible interpretation for
force hindering the browning process and attenuating negative results under energetic challenges to some extent.
the effects of energetic challenges on browning and
thermogenesis. Once adipocytes enter the buffer zone
due to the aforementioned or other extrinsic (e.g. season; Remodelling of the thermogenic system under
Au-Yong et al., 2009; Kern et al., 2014; Yoneshiro et al.,
energy challenges
2016) and intrinsic (e.g. sex difference; Cypess et al., 2013;
Kaikaew et al., 2021; van den Beukel et al., 2015) factors, Complementary relationship between NST and ST.
there may be no significant cellular changes. Unlike cold If increased adipose tissue browning and thermo-
stress that can consistently impose an energetic challenge, genic activity are considered adaptations in response
exercise and CR are relatively lower energetic challenges, to energetic challenges, it is important to have a
as exercise is an intermittent intervention and CR mainly comprehensive understanding of their physiological
reduces energy intake (note that CR also attenuates energy significance. This problem should be resolved from
expenditure as a compensatory mechanism to decreased the relationship between NST and ST. ST generates
energy intake, but this part is limited; Hill et al., 1985). heat through involuntary muscle contraction, which is
Therefore, some potential barriers (reduced exercise, the major source of heat production in adults (U Din
et al., 2016). NST occurs in adipose tissue in many different pathways: first, activated sympathetic pre-
forms, generally divided into UCP1-dependent and motor neurons stimulate the sympathetic preganglionic
UCP1-independent (futile creatine cycling (Kazak et al., neurons in the intermediolateral nucleus to activate BAT;
2015), lipid cycling (Mottillo et al., 2014) and calcium second, premotor neurons in this same medullary region
cycling (Ikeda et al., 2017)). A thorough review of NST in provide excitatory input to somatomotor neurons in the
muscles is beyond the scope of this particular review and ventral horn, which activate α and γ motor neurons
we refer readers to other reviews for in-depth discussion needed for shivering (Morrison, 2018; Nakamura, 2011;
(Blondin & Haman, 2018). Both ST and NST engage Tanaka et al., 2006) (Fig. 2). Under mild cold stress,
in thermoregulation. Although ST generates most of heat produced by NST is sufficient to maintain the core
the heat in adults, a greater contribution of NST may be temperature, but as temperature decreases progressively
favoured in the early stages of mild cold stress and thermo- to the shivering threshold, ST is activated to generate
regulation (Vybíral et al., 2000). The available data suggest more heat to avoid hypothermia (Acosta et al., 2018). A
that there is a complementary relationship between dual prospective study comparing the NST and ST capacity
thermogenic pathways (Blondin et al., 2014; Gosselin & across different ethnic groups showed that lean South
Haman, 2013; Ouellet et al., 2012; Wakabayashi et al., Asian males had smaller BAT volume and a 25% reduction
2020). The SNS mediates both NST and ST but through in resting energy expenditure (1297 kcal vesus 1689 kcal
Figure 2. Cold-induced neuroregulatory switches of ST and NST as well as the remodelling of thermo-
genic pattern
Cooling information is transmitted to the preoptic area (POA) to generate outputs that excite
thermogenesis-promoting neurons in the dorsomedial hypothalamus and dorsal hypothalamic area (DMH/DA).
These neurons in the DMH/DA provide distinct excitatory drives to BAT sympathetic premotor neurons and to
skeletal muscle shivering premotor neurons in the rostral raphe pallidus (rRPa). These, in turn, project to BAT
sympathetic preganglionic neurons (SPNs) in the intermediolateral nucleus (IML), and to α and γ motoneurons
in the ventral horn (VH) of the spinal cord, respectively (see Morrison, 2018). B, before cold adaption, shivering
thermogenesis (ST) is highly activated while the sympathetic nervous system (SNS) releases less noradrenaline
(NA) to initiate non shivering thermogenesis (NST). C, energetic challenges (mainly cold, as there is few evidence
for exercise and caloric restriction) remodel thermogenic systems of muscle and adipose tissue. D, after cold
adaption, neurons that control shivering attenuate excitatory output while those controlling NST release more
NA to activate NST. The adipose tissue also releases zinc ion which in turn reinforces SNS activation. Meanwhile,
muscle promotes adipose tissue browning and thermogenesis by regulating the levels of various myokines (FGF21,
irisin and musclin). E, finally, the remodelled thermogenic system increases thermogenic endurance and fatty acid
utilization, saves more glucose for important organs (such as brain) and reduces the disturbance of shivering to
voluntary movement. Created with BioRender.com.
per day) than matched lean Caucasian males in warm where skeletal muscle ‘entrusts’ thermogenic tasks to
condition. But they had a higher shivering threshold when adipose tissue may be one of the factors that allows
exposed to cold (Bakker et al., 2014). Gordon et al. (2019) the organism to maintain a stable temperature even
reported that 7 days of cold exposure decreased shivering after cold acclimation reduces ST. In the light of the
intensity but increased NST in adult men. Coherently, cold aforementioned conclusions, cross-talk between the
acclimation attenuated shivering intensity and enhanced skeletal muscle and adipose tissue further reinforces
the efficiency of muscle oxidative phosphorylation, the complementary mechanism between ST and NST
suggesting a reduction in muscle NST driven by proton (Fig. 3). Given that changes in the relative contributions
leakage, while BAT volume and oxidative metabolism of high intensity bursts and continuous low-intensity
were significantly increased (Blondin, Daoud, et al., shivering do not seem to affect total thermogenic cost
2017). Shifts in the thermogenic capacity of different (Haman et al., 2004), it is not surprising that ST and
organs might indicate that cold acclimation partly NST can also be modified delicately without changing
transfers the hub of thermogenesis from muscle to whole-body energy expenditure (Blondin, Daoud, et al.,
BAT. In turn, inhibiting triglyceride lipolysis in BAT 2017; Blondin, Frisch, et al., 2017). This is reminiscent
dampened cold-induced oxidative metabolism and of the ‘size principle’ of motor unit recruitment during
thermogenesis, but this was accompanied by increased exercise (Henneman et al., 1965), which allows for precise
shivering intensity and a greater reliance on glycolytic regulation of exercise (or thermogenesis) with lower
muscle fibres for thermogenic activity (Blondin, Frisch, energy consumption, ultimately achieving the desired
et al., 2017). Therefore, suppressing energy sources of exercise (or thermogenesis) outcome while optimizing
NST would lead to ST bearing more of the thermogenic energy usage. In addition, severe muscle dysfunction is
burden and aggravating glucose consumption. Despite always associated with increased adipose tissue browning
the anatomical, functional and fat content differences and thermogenesis under cachexia (Petruzzelli et al.,
between rodents and human, there remains a reciprocal 2014; Wang et al., 2017). Although these phenomena
relationship between NST and ST. Adipose-specific have been characterized extensively, no studies have yet
mTORC2 knockout mice reduced total UCP1 expression been conducted to explain whether cachexia-associated
levels and the thermogenic capacity in BAT and iWAT adipose tissue browning and thermogenesis (NST) is to
upon cold exposure, but the compensatory increase in compensate for impaired muscle thermogenic function
ST resulted in unaltered total energy expenditure (Castro (ST), which is an intriguing problem that may yield
et al., 2021). On cold acclimation at 4°C for 4 weeks, therapeutic strategies for future cachexia treatment.
NA-induced NST was elevated in rats, as expected with Therefore, the complementary mechanism between
a significant decrease in shivering activity, whereas ST and NST plays a pivotal role in maintaining stable
treatment with propanolol, a β-AR blocker, enhanced core temperature and thermogenic balance. Then again,
ST and eliminated differences in thermogenesis (Moriya going back to the question raised above, What is the
et al., 1988). physiological significance of adipose tissue browning and
The evidence underpinning this complementary thermogenesis under energetic challenges? Given the
relationship is also reflected at a molecular level. Skeletal respective characteristics of ST and NST, we envisage
muscle-specific depletion of FUNDC1, a regulator of several potential aspects and propose an answer: to
mitophagy, impaired muscle mitochondrial energetics remodel the thermogenic system so it is more economical
and elevated mitochondrial ROS, which promoted the (Fig. 4).
release of muscle-derived FGF21. A subsequent FGF21
and FUNDC1 double knockout experiment demonstrated
that it was FGF21 that linked the cross-talk between Energy saving. ST generates heat through involuntary
the skeletal muscle and adipose tissue thermogenesis contraction of muscles. On account of the cost
(Fu et al., 2018). Similarly, mitochondrial proteostasis of activating higher myoelectric activity and ATP
imbalance in skeletal muscle led to the release of FGF21 consumption during every contraction cycle, using
and GDF15, which subsequently upregulated adipose twitch-fibres for ST is energetically much more expensive
tissue thermogenesis to protect against obesity (Guo (Hohtola, 1981). This view can be defended to some
et al., 2022). These results highlight that impaired muscle extent with regard to the occurrence of mechanisms of
mitochondrial energetics may trigger compensatory NST and ST currently known. As NST uncouples the
thermogenesis in adipose tissue. Lee et al. (2014) proton gradient from ATP synthesis to produce heat
revealed that the secretion of irisin was proportional (i.e. reduces ATP generation) – known as the ‘proton
to the shivering intensity, even similar to the magnitude leak’ – ST not only utilizes the proton motive force to
stimulated by exercise. That is, the higher shivering produce ATP, but subsequently consumes energy for
intensity would lead to a larger impact on adipose contraction and has more ATP-consuming processes.
tissue browning and thermogenesis. The phenomenon Nevertheless, only circumstantial evidence is available, as
the pressing challenge lies in how to precisely measure the regulatory shift from ST to NST, as well as from periphery
thermogenic cost of NST and ST. During the course of to centre to centralize thermoregulation. Notably, a more
evolution, it is possible there was more reliance on NST or economical thermogenic system can also be achieved
lower shivering intensity to establish a more economical by establishing a more efficient ST (e.g. changing fuel
thermogenic system, which is conducive to conserving selection in skeletal muscle and improving cardiovascular
energy in the context of high energetic metabolism efficiency) without altering NST (Roussel et al., 2020).
(Blondin et al., 2014; Hohtola, 1981). This could explain Therefore, the reliance on NST or low ST is crucial for
the observations in many studies that a characteristic establishing an economical thermogenic system in the
of cold adaptation is manifested in increased NST and context of high energy and thermogenic demand. This
decreased ST, or reduced shivering intensity (Barre phenomenon has been discovered in different species,
et al., 1985; Gordon et al., 2019; Griggio, 1988; Moriya indicating a potentially conserved adaptation to energetic
et al., 1988; Teulier et al., 2010). Consistent with the challenges throughout evolution. Direct evidence for this
finding that cold transferred the hub of thermogenesis hypothesis comes from a study of UCP1 genotypes and
to BAT (Blondin, Daoud, et al., 2017), Brazaitis et al. NST capacity in populations at different latitudes. The
(2014) reported that cold acclimation elicited a thermo- frequency of haplotypes with the highest NST capacity
Figure 3. Remodelled molecular pathway for thermogenic adipocytes under cold stress
A, SNS releases more NA acting on adrenergic receptors, which subsequently activates the cAMP/PKA pathway. PKA
promotes adipocytes to secrete zinc ions, which reinforces SNS activation through zinc transporter 1 (ZnT1), and
increases PGC1α to stimulate mitochondrial biogenesis and thermogenic gene (UCP1) expression. Cold adaption
attenuates shivering thermogenesis in muscle, while modulating myokine (FGF21, irisin and musclin) secretion
to enhance NST in adipose tissue. Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated
cAMP/PKA-dependent thermogenesis in beige adipocytes. Cold decreases musclin levels and enhances FGF21
and irisin to promote adipose tissue browning and thermogenesis. FGF21 and irisin modulate thermogenesis and
browning programs by regulating downstream thermogenic factor expression. B, cold changes the fuel selection
of thermogenesis. Glucose fuelling for thermogenesis is reduced but fatty acid uptake and oxidation are enhanced.
Moreover, more glucose ends up as a carbon source supporting de novo lipogenesis that provides fatty acids (FA) for
intracellular thermogenesis and other thermogenic adipocytes. The width of arrows represent different metabolic
rates of glucose and FA. Mechanically, cold induces the combination of serine/threonine kinase 2 (AKT2) with
carbohydrate response element binding protein (ChREBP) to facilitate the transformation of glucose to triglycerides
in thermogenic adipocytes. Created with BioRender.com.
in the UCP1 region (39.4 kb) was significantly correlated thermogenesis, based on cross-talk among organs, is
with latitude and ambient temperature, which implied undoubtedly a more advanced and complex mechanism,
that increased UCP1-dependent NST might be part of however, providing larger mammals including humans
an evolutionary adaptation to cold (Nishimura et al., with the aptitude to survive the tremendous energetic
2017). Additionally, Monodelphis domestica (Didelphidae, challenges.
Marsupialia) heavily relies on skeletal muscle for heat
generation as it lacks BAT. A fast-to-slow transition in Greater preference for lipids in fuel selection. Muscle
fibre types and elevated oxygen consumption indicated contraction during ST consumes a combination of
remodelled thermogenesis in skeletal muscle under cold carbohydrates (CHO), lipids and proteins, and the
condition, but cold acclimation still led to a 15% increase thermogenic contributions of the three energy substrates
in the cost of transport (Schaeffer et al., 2005). Cost of vary with the shivering intensity, which is termed ‘fuel
transport is a measure of the energy required to move selection’ (Blondin et al., 2014). This resembles different
a given body mass a given distance (typically expressed metabolic rates of the three energy substrates under
as ml O2 kg−1 m−1 ), mainly reflecting the efficiency different exercise intensities (Brooks & Mercier, 1994),
of converting chemical energy into mechanical energy only the crossover point of substrate utilization is lower
(Taylor et al., 1982). Contrary to evidence from human during shivering (∼20% V̇O2 max ) than during exercise
studies suggesting that it is possible to maintain a constant (∼60% V̇O2 max ) (Haman et al., 2005). Emerging evidence
total thermogenic cost by regulating the contributions of indicates that glucose supports 20–80% of the whole
NST and ST, it appears that thermogenic remodelling heat produced (Haight & Keatinge, 1973) and glucose
in skeletal muscle alone is not enough to generate oxidation progressively serves as the main energy source
sufficient heat. Therefore, additional energy expenditure to sustain thermogenesis as shivering intensifies (Haman
is necessary to maintain body temperature. Given that et al., 2004, 2005). Whereas lipid oxidation dominates
metabolic rate increases with body size (Speakman, below 50% of maximum shivering intensity (∼20%
2005), one could then extrapolate that this part of extra V̇O2 max ), its contribution to thermogenesis decreases
energy expenditure would be more expensive in larger with increasing shivering intensity (Haman et al., 2005).
mammals such as humans. But humans appear to establish A thorough discussion of shivering intensity and fuel
a more economical thermogenic system to conserve this selection has been conducted in other reviews (Blondin
extra cost through coordinating thermogenesis between et al., 2014). Therefore, greater reliance on glucose is the
adipose tissue and skeletal muscle. The remodelled primary energy source for maintaining higher ST.
Figure 4. Theoretical sketch of skeletal muscle and fat thermogenic system remodelling under energetic
challenges
Decreased energy reserves caused by energetic challenges lead to a remodelled thermogenic pattern. The
remodelled thermogenic system downregulates the proportion of ST and enhances adipose tissue browning and
thermogenesis, which enables the whole thermogenic system to rely more on NST for thermoregulation. The obese
and lean body size represent high and low energy reserves, respectively. Created with BioRender.com.
Unlike ST, mounting evidence suggested that the large and voluntary movement for a common neuromuscular
energy demand of NST is covered by burning off lipids circuit (Berger, 1975; Lomax & Schönbaum, 1990;
as heat (Blondin et al., 2015; U Din et al., 2016). Meigal, 2002). For example, tonic immobility (associated
Oral administration of nicotinic acid, an inhibitor of with regulation of postural muscle tonus) temporarily
intracellular triglyceride lipolysis, dramatically reduced suppressed shivering in birds (Hohtola, 1981). Therefore,
cold-induced oxidative metabolism in BAT, indicating severe ST may impair normal performance when it occurs
that NST in BAT largely depended on fatty acid oxidation in muscle groups that modulate posture and movement.
for energy supply (Blondin, Frisch, et al., 2017). Similarly, Deep central muscles located in the neck, back and inner
WAT-derived free fatty acids (FFAs) during fasting thigh are the largest contributors to muscle glucose uptake
supported NST and served as the nutrient supply for BAT upon cold exposure due to their pivotal thermogenic roles
(Schreiber et al., 2017). Flachs et al. (2017) highlighted in ST (Blondin et al., 2015), but simultaneously, these
that triacylglycerol (TAG)/fatty acid (FA) cycling and de parts highly engage in maintaining body posture and
novo lipogenesis in WAT, together with very-low-density movement. In the competition between the thermogenic
lipoprotein–TAG synthesis in liver, provided FA as the fuel role and primary function of muscle, high intensity ST
for cold-induced NST. Therefore, FA oxidation dominates unequivocally disturbs voluntary movement. In turn,
the energy supply for NST and low intensity ST, whereas inhibiting ST might improve performance but lead to
glucose accounts for maintaining high intensity ST. As hypothermia (Israel et al., 1993; Pozos & Wittmers, 1983).
noted above, the remoulded thermogenic system tends Cold-acclimated UCP1-KO mice showed the severe PKA
to enhance NST and low intensity ST that favour FA hyperphosphorylation of ryanodine receptor 1 (RyR1)
oxidation. Since CHO contributes only about 1% to and deletion of calstabin1 in the soleus muscle was
total energy reserves and its complete oxidation produces involved in shivering, along with a dramatic reduction
only 17.3 kJ g−1 , far less than the energy potential of in SR Ca2+ release and strength during contraction.
fat (37.7 kJ g−1 ), shifts in fuel utilization may greatly However, Ca2+ release and muscle strength did not
increase thermogenic endurance, which is of considerable change in non-shivering flexor digitorum brevis muscle,
significance for survival under energetic challenges. On except for a slight impact on RyR1 complexes. These
the other hand, some glucose-obligate organs and cells results demonstrated that UCP1-mediated NST reduced
only generate ATP through glycolysis (e.g. the brain and the need for shivering and alleviated the dysfunction in
mature red blood cells) (Spitzer, 1973), and increasing shivering muscle (Aydin et al., 2008). The relationship
FA oxidation to fuel thermogenesis is conducive to between shivering and voluntary movement has been
reducing the depletion of glycogen and thus sparing pre- reviewed in several works (Meigal, 2002; Shephard, 1985).
cious glucose for more crucial physiological activities. An Evidence suggested that shivering might perturb the
adaptive response of progressively elevated FA oxidation coordination between movements during exercise (such
was also observed with longer (4 h) cold exposure as coordinating arm and breathing movements during
(Tikuisis et al., 2002). Moreover, under chronic cold swimming), and hasten the onset of fatigue and the
challenge, most glucose ends up as a carbon source to depletion of energy and water (Shephard, 1985). Thus,
support de novo lipogenesis which provides FA for intra- another implication of remodelling the thermogenic
cellular thermogenesis and other thermogenic adipocytes system lies in avoiding the impact of high ST on voluntary
(Jung et al., 2021). So changes in fuel selection may movement by enhancing NST and low intensity ST.
be more pronounced in the face of long-term energetic Taken together, the remodelled thermogenic system
challenges (Fig. 3). Overall, shifts in fuel selection serve enables the organism to maintain normothermic body
as the second part of the remodelled thermogenic system. temperature at a reduced cost. This adaptation allows
The flexible utilization of the three energy substrates an organism to continue operating with lower energy
is the key to maintaining the energy balance among consumption even after removing energetic challenges.
various physiological activities, so that each biological For example, the core temperature of winter swimmers
process possesses sufficient energy to proceed orderly is lower than that of normal people in a thermal
under energetic challenges. comfort state (Soberg et al., 2021), and exercise-trained
mice possess decreased resting metabolic rate during
Reducing interference with voluntary movement. the daytime (rest/inactivity phase) than their sedentary
Although ST is a rapid and efficient pathway to generate counterparts (Raun et al., 2020). Therefore, less energy
heat, the primary physiological role of skeletal muscle may be consumed in sustaining body temperature.
is sustaining posture and generating movement via All these remodelled physiological activities direct the
continuous and smooth contraction and relaxation. organism towards an energy-saving pattern, ultimately
Involuntary contractions of ST are not intended for gaining a higher chance of survival when coping with
movement and may compete with postural muscle tonus energetic challenges (Fig. 2).
Conclusion Abe, Y., Fujiwara, Y., Takahashi, H., Matsumura, Y., Sawada,
T., Jiang, S., Nakaki, R., Uchida, A., Nagao, N., Naito,
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metabolic diseases in recent years. Nevertheless, it must demethylase JMJD1A coordinates acute and chronic
be realized that these approaches do not have the same adaptation to cold stress via thermogenic phospho-switch.
targeting characteristics as drugs, but tend to act on the Nature Communications, 9(1), 1566.
whole organism, so the ultimate effect is an integrated Acosta, F. M., Martinez-Tellez, B., Sanchez-Delgado, G.,
result of complex physiological activities. Therefore, Alcantara, J., Acosta-Manzano, P., Morales-Artacho, A. J.,
when we attempt to regulate energy metabolism through & Ruiz, J. R. (2018). Physiological responses to acute cold
exposure in young lean men. PLoS ONE, 13(5), e196543.
creating energetic challenges, drawing conclusions from
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compensatory or counteracting effects in other tissues. not induce browning at thermoneutrality and induces a
Here we have reviewed several interventions that influence muscle-like signature in brown adipose tissue. Frontiers in
adipose tissue whitening and browning, and questioned Endocrinology (Lausanne), 11, 97.
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Additional information Fundamental Research Funds for the Central Universities and
The Key Laboratory of Adolescent Health Assessment and
Competing interests Exercise Intervention (Ministry of Education).
The authors declare no competing interests.
Keywords
Author contributions adipose tissue, browning, energetic challenges, skeletal muscle,
Y.Z. and Z.Q. conceptualized the manuscript. Y.Z.wrote the first whitening
draft of the manuscript; Z.Q. and W.L. reviewed and modified
the manuscript. All authors have read and approved the final
Supporting information
version of this manuscript and agree to be accountable for all
aspects of the work in ensuring that questions related to the Additional supporting information can be found online in the
accuracy or integrity of any part of the work are appropriately Supporting Information section at the end of the HTML view of
investigated and resolved. All persons designated as authors the article. Supporting information files available:
qualify for authorship, and all those who qualify for authorship
are listed. Peer Review History
Funding
This research was funded by the National Natural Science
Foundation of China (grant number 32271174), and the

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J Physiol 602.

Adipose tissue browning and thermogenesis under

Handling Editors: Laura Bennet & Jean-Claude Béïque

Introduction the browning of adipose tissue and activation of BAT

Ambient Protocols/pathological Adipose tissue browning or whitening

High energetic challenges

Ambient Protocols/pathological Adipose tissue browning or whitening

Humans CR for 8 weeks (3.3–4.2 Browning markers (UCP1, PGC1α,

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