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Exercise remodels subcutaneous fat tissue and improves metabolismHarriet Wallberg-Henriksson and Juleen R. Zierath

Refers to Stanford, K. I. et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes doi:10.2337/db14-0704

Exercise training is one of the key interventions for preventing and treating type 2 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 ‘exercise-trained’ subcutaneous adipose tissue might also have an important role in enhancing glucose homeostasis.

Regular physical activity enhances whole-body 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 pro-motes glucose transport and enhances insulin-stimulated glucose uptake and metabolism, even in severe type 1 diabe-tes mellitus and type 2 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 insulin-stimulated glucose transport and metabo-lism in isolated adipocytes,4 which indicates that exercise training enhances insulin sen-sitivity in both skeletal muscle and adipose tissue. A new report by Stanford and col-leagues suggests that subcutaneous adipose tissue also has an important endocrine role in enhancing whole-body glucose homeo-stasis in response to exercise training, even in states of obesity.5

Adipose tissue has a crucial role in meta-bolic homeostasis by storing fat for long-term survival and by acting as an endocrine organ to regulate and perfect an array of processes that control whole-body metabo-lism.6 The metabolic properties of white adipo cytes can be influenced by their spe-cific 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 compart-ment has little effect. Subcutaneous adipose tissue acts as an endocrine organ to enhance insulin sensitivity by producing and releas-ing substances that systemically improve

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 addi-tion, 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 over-lapping, gene expression patterns co mpared with those of brown adipocytes and seem to have a role in energy storage and thermo-genesis in response to appropriate sig nals.6 Nevertheless, the role of brown and beige adipocytes in the adaptive response to ex ercise has been elusive.

The study reported by Stanford et al.5 provides evidence that transplantation of subcutaneous adipose tissue from exercise-trained mice into the visceral cavity of sed-entary mice improves glucose tolerance and enhances insulin sensitivity (Figure 1). This effect was also observed when subcutane-ous 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

Brown adipocyte

Subcutaneous adipose tissue

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Nature Reviews | Endocrinology

a bSedentary mice Exercise-trained mice

Adipokines

Liver Skeletalmuscle

Adipokines

Factor XGlucoseuptake

Glucoseuptake

Oxidativeskeletal muscle

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Brown adipocyte

Blood vessel

Mitochondrion

White adipocyte Subcutaneous adipose tissue

Beige adipocyte

Figure 1 | Exercise training remodels subcutaneous adipose tissue and improves glucose 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 (factor X) and a concomitant increase in glucose uptake in oxidative skeletal muscle and brown adipose tissue.

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that exercise training ‘remodels’ subcutane-ous adipose tissue into a more metabolically active tissue. Indeed, the mRNA expres-sion profile of subcutaneous adipose tissue from exercise-trained mice was enriched in genes encoding beige adipocyte markers and regu lators of mitochondrial bio genesis (such as Ucp1, Prdm16, Cidea, Elovl3, Ppargc1a, Tfam and Cs, among others).5 Stanford and colleagues attribute the pro-found effect of ‘exercise-trained’ subcutane-ous 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 factor 21 (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 unequivo-cally prove that FGF21 is the systemic factor responsible for the improvements in glucose homeostasis, they found that glucose uptake in brown fat tissue and oxi-dative 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 appear-ance of beige adipocytes interspersed within subcutaneous adipose tissue and concomi-tantly induces the production of a systemic factor that enhances glucose uptake in skel-etal muscle and brown fat tissue (Figure 1). Stanford et al. have advanced the field by highlighting the profound effect of exercise training on the remodelling of subcutane-ous adipose tissue; the authors, however, fall short in identifying the precise molecu-lar 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 col-leagues 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 cold6 indicates that these modifications are dynamic and even reversible. Stanford et al.5 report that after 11 days of endur-ance 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 14 days and completely lost after 28 days without exercise, which is consistent with earlier studies reporting increased adipo-cyte size and rapidly diminished insulin sensitivity on glucose uptake and glucose oxidation within 9 days 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 active phenotype.

The findings by Stanford et al.5 indi-cate that subcutaneous adipose tissue can partly contribute to the health-promoting effects of exercise, at least in healthy mice. The translational importance of these find-ings for the treatment of humans with insulin resistance is uncertain. Whether subcutane ous adipose tissue from exercise-trained obese or insulin-resistant mice has similar benefits also remains to be deter-mined. Given that the majority of over-weight individuals or those with type 2 diabetes mellitus who participate in exer-cise training programmes have characteris-tic insulin resistance in skeletal muscle and adipose tissues, the adaptability of these tissues might be compromised. Future work to identify the molecular nature of

the insulin-sensitizing factor(s) secreted from exercise-trained subcutaneous adipo-cytes might reveal novel therapies for the manage ment of insulin resistance in obesity or type 2 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 väg 4a, SE 171 77 Stockholm, Sweden. Correspondence to: J.R.Z. juleen.zierath@ki.se

AcknowledgementsThe 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 interestsThe authors declare no competing interests.

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5. Stanford, K. I. et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes http://dx.doi.org/10.2337/db14–0704.

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8. Enerback, S. The origins of brown adipose tissue. N. Engl. J. Med. 360, 2021–2023 (2009).

9. Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).

10. Craig, B. W., Thompson, K. & Holloszy, J. O. Effects of stopping training on size and response to insulin of fat cells in female rats. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 54, 571–575 (1983).

Published online 24 February 2015; doi:10.1038/nrendo.2015.24

‘‘…the adaptive response to exercise training involves the integrated biology of numerous cells, tissues and organs’’

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