YAP and TAZ protect against white adipocyte cell death during obesity

Wang, Lei; Wang, Shengpeng; Shi, Yue; Li, Rui; Günther, Stefan; Ong, Yu Ting; Potente, Michael; Yuan, Zuyi; Liu, Enqi; Offermanns, Stefan

doi:10.1038/s41467-020-19229-3

Cited by 38 publications

(36 citation statements)

References 84 publications

(122 reference statements)

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“…Mechanistically, downstream of RhoA/ROCK-mediated F-actin assembly, nuclear translocation of MRTF-A suppresses the expression of IRS1 and PPARγ in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance ( 116 ). Moreover, RhoA/ROCK-mediated actomyosin contractility promotes nuclear translocation of the transcriptional co-activators YAP/TAZ which suppress expression of pro-apoptotic factor Bim and protect against white adipocyte cell death during obesity ( 177 ).…”

Section: Cellular Actions Of Rock Signaling Pathways In Adipose Tissuementioning

confidence: 99%

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Wei

Shi

2022

Front. Endocrinol.

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Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

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Section: Cellular Actions Of Rock Signaling Pathways In Adipose Tissuementioning

confidence: 99%

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Wei

Shi

2022

Front. Endocrinol.

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“…Yap has a crucial role in cell survival (Wang et al, 2020; Yosefzon et al, 2018), and an increase in cell death in yap single and double mutants has been reported in post-gastrulating embryos at stage 20-22 (Porazinski et al, 2015; Vazquez-Marin et al, 2019). Therefore, we first evaluated if a possible explanation for the observed phenotype was an increase in cell death in yap double mutants during gastrulation.…”

Section: Resultsmentioning

confidence: 99%

A Yap-dependent transcriptional program directs cell migration for embryo axis assembly

Sousa-Ortega

Vázquez-Marín

Sanabria-Reinoso

et al. 2022

Preprint

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The condensation of the embryo primary axis is a fundamental landmark in the establishment of the vertebrate body plan. Although the complex morphogenetic movements directing cell convergence towards the midline have been described extensively, little is known on how gastrulating cells interpret mechanical cues. Yap proteins are among the best characterized transcriptional mechanotransducers, yet their role in gastrulation has remained elusive. Here we show that the double knockout of yap and its paralog yap1b in medaka results in an axis assembly failure. Quantitative live imaging reveals that mutant cells display reduced displacement and migratory persistence. By characterizing the Yap-dependent transcriptional program, we identified genes involved in cytoskeletal organization and cell-ECM adhesion, rather than in germ layer specification, as direct Yap targets. Dynamic analysis of Tead sensors and downstream targets reveals Yap is acting in migratory cells, and not as a midline beacon, to direct gastrulating precursors trajectories by promoting cortical actin recruitment and focal adhesions assembly. We propose that Yap is engaged in a mechano-regulatory loop that is essential to maintain the directed cell migration sustaining embryo axis formation.

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“…Interferometric phase microscopy revealed that lipid droplets in adipocytes are stiffer than in cytoplasm, which suggests lipid droplets mechanically distort internal environments [ 33 , 49 ]. Furthermore, droplet stiffness increases with size and leads to cytoskeletal and nuclear rearrangements.…”

Section: Discussionmentioning

confidence: 99%

YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity

et al. 2022

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Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.

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YAP and TAZ protect against white adipocyte cell death during obesity

Cited by 38 publications

References 84 publications

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

A Yap-dependent transcriptional program directs cell migration for embryo axis assembly

YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity

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