Editors' ChoiceMetabolic Disease

When fat is beneficial

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Science Translational Medicine  13 Mar 2019:
Vol. 11, Issue 483, eaax0874
DOI: 10.1126/scitranslmed.aax0874

Abstract

In response to exercise, adipose tissue secretes TGF-β2 that improves metabolic health.

Obesity and physical inactivity are associated with the development of chronic metabolic disorders such as insulin resistance, type 2 diabetes, and cardiovascular disease. Regular exercise has significant metabolic benefits: increasing glucose tolerance, improving lipid profile, enhancing blood pressure control, and maintaining body composition. In addition to stimulating skeletal muscle glucose uptake and aerobic capacity, exercise exerts beneficial effects in adipose tissue including increased metabolic activity and mitochondrial function. However, the molecular mechanisms by which adipose tissue contributes to exercise-induced metabolic improvement are largely unknown. The study by Takahashi et al. provides insights into exercise and identifies transforming growth factor β-2 (TGF-β2) as an exercise-induced adipokine that improves metabolic health.

Using microarray analyses, the authors first found that moderate-intensity cycling exercise increased TGF-β2 mRNA specifically in subcutaneous white adipose tissue (scWAT) of human subjects and mice. They hypothesized that TGF-β2 acts as an adipokine because plasma TGF-β2 concentrations correspondingly increased with exercise training. scWAT transplant experiments and exercise studies in adipose-specific Tgf −/− mice revealed that TGF-β2 contributes to exercise-induced metabolic improvements. Further, they showed that treatment of obese mice with TGF-β2 improved glucose tolerance, enhanced insulin sensitivity, increased insulin-stimulated glucose uptake in muscle, and decreased adipose tissue inflammation without altering body weight or food intake. TGF-β2 treatment also increased fatty acid uptake, resulting in decreased plasma-free fatty acid concentrations. Exercise training increased TGF-β2 expression through a pathway involving lactate-mediated peroxisome proliferator activated receptor α (PPARα) expression in scWAT.

These results enhance our understanding of how exercise improves metabolism and identify TGF-β2 as a promising therapeutic target that mediates inter-organ communication. TGF-β2 is a key cytokine that exerts immunosuppressive effects and is frequently overexpressed in malignant tumors; however, short-term TGF-β2 treatment of mice did not result in pathological findings. If future studies demonstrate its long-term safety and effectiveness, TGF-β2 treatment could hold potential as a therapeutic tool for metabolic disease.

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