Atf3 induction is a therapeutic target for obesity and metabolic diseases

Kim, Suji; Song, No-Joon; Bahn, Gahee; Chang, Seo-Hyuk; Yun, Ui Jeong; Ku, Jin‐Mo; Jo, Dong-Gyu; Park, Kye Won

doi:10.1016/j.bbrc.2018.09.048

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…Further studies to elucidate the signaling pathways and the mechanisms through which ATF3 or ATF3 inducer ST32da regulates the metabolism of brown and beige adipocytes are required. Kim et al demonstrated that treatment with chalcones, including 2,2,4-trihydroxychalcone and butein, results in vigorous induction of ATF3 and suppression of C3H10T1/2 cell differentiation (44). In summary, these findings indicate that ATF3 plays a coordinating role in inhibiting adipogenesis and lipogenesis, yet to promote beige and brown cell differentiation through white adipocyte browning (Figure 2).…”

Section: Role Of Atf3 In Adipose Tissuementioning

confidence: 86%

Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer

2020

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Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays vital roles in modulating metabolism, immunity, and oncogenesis. ATF3 acts as a hub of the cellular adaptive-response network. Multiple extracellular signals, such as endoplasmic reticulum (ER) stress, cytokines, chemokines, and LPS, are connected to ATF3 induction. The function of ATF3 as a regulator of metabolism and immunity has recently sparked intense attention. In this review, we describe how ATF3 can act as both a transcriptional activator and a repressor. We then focus on the role of ATF3 and ATF3-regulated signals in modulating metabolism, immunity, and oncogenesis. The roles of ATF3 in glucose metabolism and adipose tissue regulation are also explored. Next, we summarize how ATF3 regulates immunity and maintains normal host defense. In addition, we elaborate on the roles of ATF3 as a regulator of prostate, breast, colon, lung, and liver cancers. Further understanding of how ATF3 regulates signaling pathways involved in glucose metabolism, adipocyte metabolism, immuno-responsiveness, and oncogenesis in various cancers, including prostate, breast, colon, lung, and liver cancers, is then provided. Finally, we demonstrate that ATF3 acts as a master regulator of metabolic homeostasis and, therefore, may be an appealing target for the treatment of metabolic dyshomeostasis, immune disorders, and various cancers.

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Section: Role Of Atf3 In Adipose Tissuementioning

confidence: 86%

Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer

2020

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“…Our survey of the levels of ATF family members in response to cold exposure and CL treatment has revealed for the first time that ATF3 is among the ATFs most highly induced at the transcriptional level by these stimuli in adipose tissue, supporting a critical role of ATF3 in the regulation of transcriptional responses to thermogenic stimuli leading to control of brown/beige fat tissue functionality. Although it has been shown that mice with total ablation of ATF3 develop obesity and insulin resistance (23) and have decreased browning (22), the genetic requirements for this transcription factor specifically in adipose tissues have not yet been investigated. Future studies involving the generation of new animal models with conditional knock out of ATF3 in adipose tissues will reveal the extent of ATF3 contribution to thermogenic functionality in fat tissues.…”

Section: Discussionmentioning

confidence: 99%

The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3

Verma¹,

Périè²,

Mueller

2020

Journal of Biological Chemistry

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Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.

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“…10d–f). A recent study showed that sulfuretin, a known phytochemical ATF3 inducer, could also counteract weight gain and improve glucose tolerance in HFD fed mice 53 . Our drug, ST32da, similar to sulfuretin, had the specificity of ATF3 induction (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte browning and resistance to obesity in mice is induced by expression of ATF3

Cheng

et al. 2019

Commun Biol

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Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 (ATF3−/−) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein–stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders.

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Atf3 induction is a therapeutic target for obesity and metabolic diseases

Cited by 16 publications

References 30 publications

Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer

Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer

The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3

Adipocyte browning and resistance to obesity in mice is induced by expression of ATF3

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