NEWS & VIEWS

METABOLISM

Exercise remodels subcutaneous

fat tissue and improves metabolism
Harriet Wallberg-Henriksson and Juleen R. Zierath
Refers to Stanford, K.I. etal. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose
homeostasis. Diabetes doi:10.2337/db140704

Exercise training is one of the key interventions for preventing and

treating type2 diabetes mellitus. Although the health-promoting effects
of exercise are largely ascribed to improvements in skeletal muscle
insulin sensitivity, new data published in Diabetes suggest exercisetrained subcutaneous adipose tissue might also have an important role
in enhancing glucose homeostasis.
Regular physical activity enhances wholebody glucose homeostasis. 1 Many of the
beneficial effects of regular physical exercise
training have been attributed to improved
insulin sensitivity in skeletal muscle. 1
Muscle contractile activity directly promotes glucose transport and enhances
insulin-stimulated glucose uptake and
metabolism, even in severe type1 diabetes mellitus and type2 diabetes mellitus.2
Although skeletal muscle has been a focus
of research in exercise biology, the adaptive
response to exercise training involves the
integrated biology of numerous cells, tissues
and organs.3 Regular exercise decreases the
size of adipose cells and increases insulinstimulated glucose transport and metabolism in isolated adipocytes,4 which indicates
that exercise training enhances insulin sensitivity in both skeletal muscle and adipose
tissue. A new report by Stanford and colleagues suggests that subcutaneous adipose
tissue also has an important endocrine role
in enhancing whole-body glucose homeostasis in response to exercise training, even
in states of obesity.5
Adipose tissue has a crucial role in metabolic homeostasis by storing fat for longterm survival and by acting as an endocrine
organ to regulate and perfect an array of
processes that control whole-body metabolism.6 The metabolic properties of white
adipocytes can be influenced by their specific regional location in the body, with
the most common classification of adipose
tissue consisting of subcutaneous fat and
visceral fat depots. Intrinsic differences

between these two depots render visceral fat

detrimental and subcutaneous fat beneficial
for whole-body metabolic regulation. This
depot specificity has become increasingly
apparent through surgical approaches,7 in
which transplantation of subcutaneous fat
tissue to the visceral compartment reduces
adiposity and improves glucose homeo
stasis, whereas transplantation of visceral
fat tissue into a subcutaneous compartment has little effect. Subcutaneous adipose
tissue acts as an endocrine organ to enhance
insulin sensitivity by producing and releasing substances that systemically improve
a Sedentary mice

glucose metabolism.6,7 Brown adipocytes

are metabolically active fat cells located in
the interscapular and perirenal regions of
rodents and the supraclavicular and spinal
regions in humans, and have an important
role in energy homeostasis via regulation
of whole-body thermogenesis. 8 In addition, brown-fat-like cells are interspersed
within white fat depots in both rodents and
humans.6 These specialized cells called beige
or bright adipocytes have distinct, yet overlapping, gene expression patterns compared
with those of brown adipocytes and seem to
have a role in energy storage and thermo
genesis in response to appropriate signals.6
Nevertheless, the role of brown and beige
adipocytes in the adaptive response to
exercise has been elusive.
The study reported by Stanford etal. 5
provides evidence that transplantation of
subcutaneous adipose tissue from exercisetrained mice into the visceral cavity of sedentary mice improves glucose tolerance and
enhances insulin sensitivity (Figure1). This
effect was also observed when subcutaneous adipose tissue from either sedentary or
exercise-trained mice was transplanted into
obese insulin-resistant mice. Conversely,
transplanted visceral adipose tissue did
not result in improved glucose tolerance or
enhanced insulin sensitivity, which suggests
b Exercise-trained mice

Mitochondrion
Subcutaneous
adipose tissue

White adipocyte
Blood vessel

Subcutaneous
adipose tissue

Beige adipocyte

Adipokines

Adipokines
+

Glucose
uptake
Liver

Skeletal
muscle

Brown adipocyte

Oxidative
skeletal muscle

Factor X

+
Glucose
uptake
Brown adipocyte

Figure 1 | Exercise training remodels subcutaneous adipose tissue

and improves
Nature
Reviews |glucose
Endocrinology
homeostasis. a | In sedentary mice, subcutaneous adipose tissue consists of classical white
adipocytes, which act as a reservoir for fat storage and typically contain large lipid droplets.
Adipokines are produced by adipocytes and released into the circulation to modify glucose and
lipid metabolism in multiple organs and tissues such as the liver, skeletal muscle and brown
adipose tissue. b | In exercise-trained mice, subcutaneous adipose tissue adopts
characteristics of beige adipocytes, including the presence of multilocular cells that contain
several lipid droplets, increased vascularization and mitochondrial enrichment. This remodelling
leads to the release of a putative endocrine factor (factorX) and a concomitant increase in
glucose uptake in oxidative skeletal muscle and brown adipose tissue.

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NEWS & VIEWS

that exercise training remodels subcutaneous adipose tissue into a more metabolically
active tissue. Indeed, the mRNA expression profile of subcutaneous adipose tissue
from exercise-trained mice was enriched
in genes encoding beige adipocyte markers
and regulators of mitochondrial biogenesis
(such as Ucp1, Prdm16, Cidea, Elovl3,
Ppargc1a, Tfam and Cs, among others).5
Stanford and colleagues attribute the profound effect of exercise-trained subcutaneous adipose tissue on glucose homeostasis
to an endocrine effect, rather than to the
ability of the transplanted tissue to take
up and store more glucose. The authors
hypothesize that increased systemic levels of
fibroblast growth factor21 (FGF21) could
mediate the reported beneficial effects on
metabolism. FGF21 is a potent metabolic
regulator known to reduce plasma levels
of glucose and triglycerides, and to protect
against dietary-induced obesity.9 Although
Stanford and colleagues did not unequivocally prove that FGF21 is the systemic
factor responsible for the improvements
in glucose homeostasis, they found that
glucose uptake in brown fat tissue and oxidative skeletal muscle was increased in mice
transplanted with exercise-trained sub
cutaneous adipose tissue. These compelling
results suggest that exercise training, by an
unknown mechanism, increases the appearance of beige adipocytes interspersed within
subcutaneous adipose tissue and concomitantly induces the production of a systemic
factor that enhances glucose uptake in skeletal muscle and brown fat tissue (Figure1).
Stanford etal. have advanced the field by
highlighting the profound effect of exercise
training on the remodelling of subcutaneous adipose tissue; the authors, however,
fall short in identifying the precise molecular mechanism orchestrating the complex
crosstalk with other metabolically active
organs. Indeed, the involvement of other
known or novel adipokines or metabolites
cannot be excluded.
One intriguing question arising from
the research reported by Stanford and colleagues is the degree of plasticity of the gene
expression profile of subcutaneous adipose

tissue and the extent to which the depot is

remodelled. Appearance of beige and brown
adipose tissue after exposure to exercise or
cold 6 indicates that these modifications
are dynamic and even reversible. Stanford
etal.5 report that after 11days of endurance exercise, subcutaneous adipose tissue
exhibits a beige phenotype, as evidenced by
the induction of numerous genes encoding
beige adipocyte markers and regulators of
mitochondrial biogenesis. Strikingly, these
adaptations were markedly reduced after
14days and completely lost after 28days
without exercise, which is consistent with
earlier studies reporting increased adipocyte size and rapidly diminished insulin
sensitivity on glucose uptake and glucose
oxidation within 9days after cessation of
exercise training.10 Whether more intense
and longer-lasting exercise training periods
result in a more pronounced appearance
of beige fat cells within subcutaneous adi
pose depots is a matter of speculation, but
clearly stimulation with regular exercise
is required to maintain a metabolically
activephenotype.

the adaptive response to

exercise training involves the
integrated biology of numerous
cells, tissues and organs

The findings by Stanford etal. 5 indicate that subcutaneous adipose tissue can
partly contribute to the health-promoting
effects of exercise, at least in healthy mice.
The translational importance of these findings for the treatment of humans with
insulin resistance is uncertain. Whether
subcutaneous adipose tissue from exercisetrained obese or insulin-resistant mice has
similar benefits also remains to be determined. Given that the majority of overweight individuals or those with type2
diabetes mellitus who participate in exercise training programmes have characteristic insulin resistance in skeletal muscle and
adipose tissues, the adaptability of these
tissues might be compromised. Future
work to identify the molecular nature of

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the insulin-sensitizing factor(s) secreted

from exercise-trained subcutaneous adipocytes might reveal novel therapies for the
management of insulin resistance in obesity
or type2 diabetes mellitus.
Department of Physiology and Pharmacology
(H.W.H.), Department of Molecular Medicine
and Surgery (J.R.Z.), Section of Integrative
Physiology, Karolinska Institutet, von Eulers
vg4a, SE 171 77 Stockholm, Sweden.
Correspondence to: J.R.Z.
juleen.zierath@ki.se
Acknowledgements
The authors acknowledge funding from The Swedish
Research Council, European Research Council,
Swedish Diabetes Association, Swedish Foundation
for Strategic Research, Strategic Diabetes Research
Program at Karolinska Institutet, Stockholm County
Council and Novo Nordisk Foundation.
Competing interests
The authors declare no competing interests.
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Published online 24 February 2015;
doi:10.1038/nrendo.2015.24

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