Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis

Zhang, Zhao; Jiang, Yiao; Su, Lijing; Ludwig, Sara; Zhang, Xuechun; Tang, Miao; Li, Xiaohong; Anderton, Priscilla; Zhan, Xiaoming; Choi, Mihwa; Russell, Jamie L.; Bu, Chun-Hui; Lyon, Stephen; Xu, Duo; Hildebrand, Sara; Scott, Lindsay; Quan, Jia; Simpson, Rochelle; Sun, Qian; Qin, Baifang; Collie, Tiffany; Tadesse, Meron; Moresco, Eva Marie Y.; Beutler, Bruce

doi:10.1016/j.cmet.2022.09.018

Cited by 8 publications

(3 citation statements)

References 40 publications

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“…For example, adipose tissue lipids are mobilized for energy production through lipolysis during acute inflammation and sepsis (Sherwood et al , 1970; Feingold et al , 1992; Jha et al , 2014), whereas catecholamine‐induced lipolysis is reduced in chronic metabolic inflammation (Mowers et al , 2013). Adding to this complex picture is that recently Ovol2 has been suggested to exert a dual role in promoting BAT‐mediated thermogenesis and inhibiting WAT adipogenesis to maintain energy balance (Zhang et al , 2022). Therefore, it remains formally possible that Ovol1/2 loss in epidermis reduces thermogenesis through a more direct mechanism, which opposes the barrier deficiency‐induced thermogenesis.…”

Section: Discussionmentioning

confidence: 99%

Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Dragan

Chen

et al. 2023

EMBO Reports

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Skin epidermis constitutes the outer permeability barrier that protects the body from dehydration, heat loss, and myriad external assaults. Mechanisms that maintain barrier integrity in constantly challenged adult skin and how epidermal dysregulation shapes the local immune microenvironment and whole‐body metabolism remain poorly understood. Here, we demonstrate that inducible and simultaneous ablation of transcription factor‐encoding Ovol1 and Ovol2 in adult epidermis results in barrier dysregulation through impacting epithelial‐mesenchymal plasticity and inflammatory gene expression. We find that aberrant skin immune activation then ensues, featuring Langerhans cell mobilization and T cell responses, and leading to elevated levels of secreted inflammatory factors in circulation. Finally, we identify failure to gain body weight and accumulate body fat as long‐term consequences of epidermal‐specific Ovol1/2 loss and show that these global metabolic changes along with the skin barrier/immune defects are partially rescued by immunosuppressant dexamethasone. Collectively, our study reveals key regulators of adult barrier maintenance and suggests a causal connection between epidermal dysregulation and whole‐body metabolism that is in part mediated through aberrant immune activation.

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Section: Discussionmentioning

confidence: 99%

Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Dragan

Chen

et al. 2023

EMBO Reports

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“…Ovol2 is highly expressed in white adipose stromal cells but not in mature white adipocytes. OVOL2 can block adipogenesis by interacting with the C-terminal portion of C/EBPα to inhibit its adipogenic function in both mouse and human adipocytes ( 34 ). The mechanism of OVOL2 in brown adipocytes remains elusive and needs more investigation.…”

Section: Factors Directly Act On Adipocytementioning

confidence: 99%

Latest advances in the regulatory genes of adipocyte thermogenesis

Nie,

Lu,

Zhang

et al. 2023

Front. Endocrinol.

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An energy imbalance cause obesity: more energy intake or less energy expenditure, or both. Obesity could be the origin of many metabolic disorders, such as type 2 diabetes and cardiovascular disease. UCP1 (uncoupling protein1), which is highly and exclusively expressed in the thermogenic adipocytes, including beige and brown adipocytes, can dissipate proton motive force into heat without producing ATP to increase energy expenditure. It is an attractive strategy to combat obesity and its related metabolic disorders by increasing non-shivering adipocyte thermogenesis. Adipocyte thermogenesis has recently been reported to be regulated by several new genes. This work provided novel and potential targets to activate adipocyte thermogenesis and resist obesity, such as secreted proteins ADISSP and EMC10, enzyme SSU72, etc. In this review, we have summarized the latest research on adipocyte thermogenesis regulation to shed more light on this topic.

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“…Lipid metabolism disorder can cause a series of pathological changes, such as hyperlipidemia, atherosclerosis, obesity, fatty liver, etc., and is even closely related to the occurrence and progression of cancer. − The 3T3-L1 preadipocyte cell line is a classical model for studying lipid metabolism, which can be induced to differentiate into typical white adipocytes. During this process, the key regulatory genes include sterol regulatory element binding protein 1c (SREBP1c), peroxide proliferation-activating receptor γ (PPARγ), CCAAT enhancer binding protein α (C/EBPα), etc. , They are all located intracellularly and can be regulated by many substances directly or indirectly. − The main action mechanisms include the interaction of compound with membrane receptors or intracellular target proteins . This means that certain modulations are dominated by chemicals that have entered the cell and interact with the targets.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Comparative Analysis of the Effect and Structure-Based Influencing Factors of Flavonols on Lipid Accumulation

Ang,

Yang,

Wang

et al. 2024

J. Agric. Food Chem.

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Flavonols represented by quercetin have been widely reported to have biological activities of regulating lipid metabolism. However, the differences in flavonols with different structures in lipid-lowering activity and the influencing factors remain unclear. In this study, the stability, transmembrane uptake ratio, and lipid metabolism regulation activities of 12 flavonol compounds in the 3T3-L1 cell model were systematically compared. The results showed that kaempferide had the highest cellular uptake ratio and the most potent inhibitory effect on adipogenesis at a dosing concentration of 20 μM, followed by isorhamnetin and kaempferol. They inhibited TG accumulation by more than 65% and downregulated the expression of PPARγ and SREBP1c by more than 60%. The other four aglycones, including quercetin, did not exhibit significant activity due to the structural instability in the cell culture medium. Meanwhile, five quercetin glucosides were quite stable but showed a low uptake ratio that no obvious activity was observed. Correlation analysis also showed that for 11 compounds except galangin, the activity was positively correlated with the cellular uptake ratio (p < 0.05, r = 0.6349). These findings may provide a valuable idea and insight for exploring the structure-based activity of flavonoids at the cellular level.

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Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis

Cited by 8 publications

References 40 publications

Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Latest advances in the regulatory genes of adipocyte thermogenesis

In Vitro Comparative Analysis of the Effect and Structure-Based Influencing Factors of Flavonols on Lipid Accumulation

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