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TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism
Open accessAbstract
Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-β2 (TGF-β2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-β2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise training increases TGF-β2 in scWAT, serum, and its secretion from fat explants. Transplanting scWAT from exercise-trained wild type mice, but not from adipose tissue-specific Tgfb2-/- mice, into sedentary mice improves glucose tolerance. TGF-β2 treatment reverses the detrimental metabolic effects of high fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-β2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-β2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through inter-organ communication with fat via a lactate-TGF-β2-signaling cycle.
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“Transforming growth factor-beta 2 (TGF-β2), an exercise-induced adipokine, is stimulated by exercise-induced lactate, enhancing glucose uptake in skeletal muscle and boosting mitochondrial function, shedding light on adipose–muscle tissue crosstalk [79] (Table 1).”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [79]
In the citing paper
“Moreover, exercise-trained WAT fosters the generation of thermogenic brown-like adipocytes with specific adipokines, including TGF-β [79], apelin, follistatin, and myostatin (Figure 3) [80,81].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [79]
In the citing paper
“Exercise-related paracrine effects are also observed in the nervous system53, adipose tissue42,54–58, bone59–61, cartilage62, extracellular matrix63,64 and the immune system65,66.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [42]
In the citing paper
“In a mouse model, specific lactate exposure in vitro and in vivo increased adipocyte expression of TGFβ2 (REF.42).”
From Exerkines in health, resilience and disease (2022) · cites this paper as [42]
In the citing paper
“in a mouse model of chronic exercise, increased adipocyte levels of TGFβ2 expression and secretion were associated with improvements in glucose metabolism, lipid oxidation and a possible reduction of adipose tissue inflammation.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [42]
In the citing paper
“Parallel findings were also observed in humans undertaking chronic exercise, albeit to a less pronounced degree than the animal model observations42.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [42]
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“Moreover, many intervention studies have shown that exercise can improve adipokine levels and has beneficial effects on the metabolism, such as the transforming growth factor-β2 (TGF-β2), an exercise-induced adipokine that improves glucose tolerance and insulin sensitivity and promotes glucose and fatty acid metabolis…”
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Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis
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Hypoxia as a Double-Edged Sword to Combat Obesity and Comorbidities
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“Exercise-induced myokines, such as irisin, lactate, and β -aminoisobutyric acid, have also been re-ported to promote the activation of brown and beige fat tissues (43), (44), (45) .”
Background
Metadata
- Authors
- Takahashi, H., Alves, C. R. R., Stanford, K. I., Middelbeek, R. J. W., Nigro, P., Ryan, R. E., Xue, R., Sakaguchi, M., Lynes, M. D., So, K., Mul, J. D., Lee, M.-Y., Balan, E., Pan, H., Dreyfuss, J. M., Hirshman, M. F., Azhar, M., Hannukainen, J. C., Nuutila, P., Kalliokoski, K. K., Nielsen, S., Pedersen, B. K., Kahn, C. R., Tseng, Y.-H., & Goodyear, L. J.
- Affiliations
- Joslin Diabetes Center (US)
- University of South Carolina (US)
- University of Turku (FI)
- University of Copenhagen (DK)
- Corresponding author
- Goodyear, Laurie J.
- ORCID
- Takahashi, Hirokazu
- Alves, Christiano R. R.
- Stanford, Kristin I.
- Middelbeek, Roeland J. W.
- Nigro, Pasquale
- Sakaguchi, Masaji
- Lynes, Matthew D.
- Mul, Joram D.
- Pan, Hui
- Dreyfuss, Jonathan M.
- Hirshman, Michael F.
- Azhar, Mohamad
- Hannukainen, Jarna C.
- Nuutila, Pirjo
- Kalliokoski, Kari K.
- Nielsen, Søren
- Pedersen, Bente K.
- Kahn, C. Ronald
- Tseng, Yu-Hua
- Goodyear, Laurie J.
- Venue
- Nature Metabolism
- Published
- 2019-02-11
- Volume
- 1
- Issue
- 2
- Pages
- 291-303
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6481955
- OpenAlex
- W2912468419
- Cited by
- 204
- References
- 66
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 34 · 2023: 31 · 2022: 31 · 2021: 33 · 2020: 22 · 2019: 10
- FWCI
- 18.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (R01HL126705, 17GRNT33650018, R01DK102898)
- Joslin Diabetes Center (P30DK36836, K23-DK114550)
- TrygFonden
- National Institutes of Health (17GRNT33650018, DK 36836, 5r01dk112283-03)
- Japan Society for the Promotion of Science (18K16208)
- National Heart, Lung, and Blood Institute (R01HL126705, R01HL138738, R01HL145064)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK112283, R01DK077097, R01DK102898, K01DK111714, K23DK114550, R01DK033201, F32DK102320, T32DK007260, R01DK101043, P30DK036836, R01DK082659, R01DK099511)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- TGF-beta2, glucose tolerance, fatty acid metabolism, subcutaneous white adipose tissue, lactate, dichloroacetate, inter-organ communication, myokines, high-fat feeding, exercise training, adipocytes
- MeSH terms
- Adipose Tissue, Animals, Fatty Acids, Glucose, Physical Conditioning, Animal, Mice, Transforming Growth Factor beta2, Adipokines
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