Abstract
Obesity is associated with energy metabolic disturbance and is caused by long-term excessive energy storage in white adipose tissue (WAT). The WAT browning potentially reduces excessive energy accumulation, contributing an attractive target to combat obesity. As a pivotal regulator of cell growth, the transcription factor E2F1 activity dysregulation leads to metabolic complications. The regulatory effect and underlying mechanism of E2F1 knockout on WAT browning, have not been fully elucidated. To address this issue, in this study, the in vivo adipose morphology, mitochondria quantities, uncoupling protein 1 (UCP-1), autophagy-related genes in WAT of wild-type (WT) and E2F1–/– mice were detected. Furthermore, we evaluated the UCP-1, and autophagy-related gene expression in WT and E2F1–/– adipocyte in vitro. The results demonstrated that E2F1 knockout could increase mitochondria and UCP-1 expression in WAT through autophagy suppression in mice, thus promoting WAT browning. Besides, adipocytes lacking E2F1 showed upregulated UCP-1 and downregulated autophagy-related genes expression in vitro. These results verified that E2F1 knockout exerted effects on inducing mice WAT browning through autophagy inhibition in vivo and in vitro. These findings regarding the molecular mechanism of E2F1-modulated autophagy in controlling WAT plasticity, provide a novel insight into the functional network with the potential therapeutic application against obesity.
Highlights
Obesity is a serious global public health problem and a preventable risk factor for hypertension, diabetes, breast cancer, and other cancers (Marie et al, 2015)
The results proved that E2f Transcription Factor 1 (E2F1) could be involved in the upregulation of autophagy-related genes in adipocytes in vitro, and E2F1 knockout inhibited autophagy activity to promote white adipose tissue (WAT) browning
uncoupling protein 1 (UCP-1) expression and beige cells formation were observed in E2F1−/− WAT in vivo and E2F1−/− adipocytes in vitro. These results demonstrated that E2F1 knockout promoted WAT browning through increasing UCP-1 expression and mitochondria, which might lead to energy expenditure in a thermogenic manner
Summary
Obesity is a serious global public health problem and a preventable risk factor for hypertension, diabetes, breast cancer, and other cancers (Marie et al, 2015). Brown adipose tissue (BAT) possesses the ability to expend energy as heat, Abbreviations: WAT, White Adipose Tissue; BAT, Brown Adipose Tissues; UCP-1, Uncoupling Protein-1; E2F1, E2f Transcription Factor 1; MAP1LC3, Microtubule-Associated Protein-1 Light Chain-3; SQSTM1/p62, Sequestosome-1; ATG, Autophagy-Related Gene; WT, Wild-Type; ADSCS, Adipose Stem Cells; FBS, Fetal Bovine Serum; PBS, PhosphateBuffered Saline; H&E, Hematoxylin-Eosin; IHC, Immunohistochemistry; TEM, Transmission Electron Microscopy; CTRP5, C1q/TNF-related protein 5. UCP-1 is located in the inner membrane of brown adipocytes mitochondria and uncouples the respiratory chain from oxidative phosphorylation through a proton conductance pathway (Villarroya et al, 2018). It is well-known that obesity is closely associated with adipose tissues, which play central roles in metabolic regulation (Kaisanlahti and Glumoff, 2019). Further research on adipose physiological effects is needed to improve the understanding of metabolism and restore metabolic health
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