Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome

Li, Shang; Zhai, Junyu; Chu, Weiwei; Geng, Xue; Chen, Zi‐Jiang; Du, Yanzhi

doi:10.1016/j.trsl.2020.02.003

Cited by 41 publications

(53 citation statements)

References 61 publications

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“…In this study, we demonstrated that DHEA-induced PCOS-like rats exhibited insulin resistance as well as arrhythmic expression of circadian clock genes in the liver and adipose, particularly showing decreased BMAL1 expression. Meanwhile, hyperandrogenism led to the negative regulation of BMAL1-induced expression of NAMPT/NAD + /SIRT1 pathway, further inhibiting downstream GLUT4 and contributing to insulin resistance in mature adipose cells, which was consistent with our previous results in HepG2 cells [10]. Thus, our study uncovered the potentially novel role of BMAL1 in the contribution of hyperandrogenism to insulin resistance in PCOS.…”

Section: Discussionsupporting

confidence: 91%

“…Rhythmic disorder in the expression of circadian genes, especially Bmal1, as well as insulin pathway genes was observed in both liver and adipose of PCOS-like rats. Our previous study has shown the decreased BMAL1 mRNA expression in PCOS patients [10]. BMAL1 plays a vital role in lipid and glucose metabolism.…”

Section: Discussionmentioning

confidence: 88%

“…Environmental risk factors combined with genetic factors give rise to hyperandrogenism and insulin resistance, both of which are known to be involved in the onset of PCOS [20]. Circadian disruption, especially constant darkness, induces insulin resistance of PCOS in rats, including increased fasting blood glucose level and increased serum insulin and leptin levels [10]. To investigate the relationship between circadian dysfunction and glucose metabolism, we used liver and adipose tissues of the DHEA-induced PCOS-like rat model as these are the two principal tissues involved in insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous work, we have certified that testosterone treatment decreases BMAL1 expression, and further reduces glucose uptake by inhibiting the NAMPT/NAD + / SIRT1 pathway and GLUT4 expression in HepG2 cells [10]. Mature adipocytes induced by the 3T3-L1 cell line are always used as the cell model for molecular research studies conferring to adipose tissue.…”

Section: Disrupted Rhythmic Expression Of Circadian Clock Genes and Imentioning

confidence: 99%

“…Mutations of the core circadian clock genes have been linked to the characteristics of the metabolic syndrome commonly associated with PCOS [9]. Our previous work has also presented that the arrhythmic expressions of circadian clock genes due to constant darkness result in the metabolic and reproductive hallmarks of PCOS in rats [10]. Reportedly, sleep disturbances are doubled in PCOS patients, and obstructive sleep apnea is a common feature of these patients.…”

Section: Introductionmentioning

confidence: 97%

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Decreased brain and muscle ARNT-like protein 1 expression mediated the contribution of hyperandrogenism to insulin resistance in polycystic ovary syndrome

Zhai

Shang

et al. 2020

Reprod Biol Endocrinol

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Background: The interface between environmental risk factors and genetic factors could contribute to the pathogenesis of hyperandrogenism and insulin resistance in polycystic ovary syndrome (PCOS); however, the underlying complex mechanism remains to be elucidated. Methods: We used dehydroepiandrosterone (DHEA)-induced PCOS-like rat model to measure circadian clock genes and insulin resistance-related genes. Additionally, we performed in vitro experiments in mature adipocytes to verify the molecular mechanisms. Results: DHEA-induced PCOS-like rats exhibited insulin resistance and arrhythmic expression of circadian clock genes in the liver and adipose tissues, particularly showing decreased brain and muscle ARNT-like protein 1 (BMAL1) expression. In addition, hyperandrogenism gave rise to negative regulation of BMAL1 expression to nicotinamide phosphoribosyltransferase and sirtuin 1, which further inhibited downstream glucose transporter type 4, leading to insulin resistance in mature adipocytes, which was consistent with our previous results in HepG2 cells. Conclusions: Decreased BMAL1 expression in the liver and adipose played a potentially novel role in the contribution of hyperandrogenism to insulin resistance, which might be a possible mechanism accounting for the pathogenesis of PCOS.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Disrupted Rhythmic Expression Of Circadian Clock Genes and Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

Decreased brain and muscle ARNT-like protein 1 expression mediated the contribution of hyperandrogenism to insulin resistance in polycystic ovary syndrome

Zhai

Shang

et al. 2020

Reprod Biol Endocrinol

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BMAL1 promotes colorectal cancer cell migration and invasion through ERK‐ and JNK‐dependent c‐Myc expression

et al. 2022

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Background Cancer metastasis is still a life threat to patients with colorectal cancer (CRC). Brain and muscle ARNT‐like protein 1 (BMAL1) is an important biological proteins that can regulate the behavior of cancer cells and their response to chemotherapy. However, the role of BMAL1 in the tumorigenic phenotype of CRC remains unclear. Here, we aim to investigate the functional role and mechanisms of BMAL1 in CRC. Methods The mRNA expression of BMAL1 was studied using the Cancer Genome Atlas (TCGA) databases. The protein level in clinical tissues was confirmed by immunohistochemistry (IHC). The effects of BMAL1 on the epithelial‐to‐mesenchymal transition (EMT) and proliferation of CRC cell lines (including BMAL1 overexpressed or silencing cells) were studied by Transwell, wound healing, CCK‐8 and colony formation experiments. A series of experiments were conducted to demonstrate the mechanisms of BMAL1 regulating EMT and cancer proliferation in vitro and in vivo. Results We found that BMAL1 expression was closely related to the poor prognosis of CRC. BMAL1 overexpression promoted cell proliferation and migration. Mechanistically, we found that BMAL1 may activate the epithelial‐to‐mesenchymal transition (EMT) pathway and induce the β‐catenin release further promotes the expression of oncogene c‐Myc and the migration of colorectal cells by activating MAPK pathway. However, BMAL1 silencing achieved the opposite effect. In addition, blocking MAPK‐signaling pathway with specific inhibitors of ERK1/2 and JNK can also downregulate the expressions of c‐Myc in vitro. Taken together, these results suggested that the BMAL1/ c‐Myc‐signaling pathway may regulate the metastasis of CRC through the JNK/ERK1/2 MAPK‐dependent pathway. Conclusions Our study showed that BMAL1 promotes CRC metastasis through MAPK‐c‐Myc pathway. These results deepen our understanding of the relationship between BMAL1 and tumorigenic phenotypes, which may become a promising therapeutic target for BMAL1 overexpressing CRC.

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Constant light exposure alters gut microbiota and short‐/medium‐chain fatty acids and aggravates PCOS‐like traits in HFD‐fed rats

Yue

Lin

et al. 2022

Obesity

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Objective This study investigated the effects of constant light exposure on polycystic ovary syndrome (PCOS)‐like endocrine and metabolic changes in high‐fat diet (HFD)‐fed rats and to elucidate the related microbiotic mechanisms. Methods A total of 32 female Sprague‐Dawley rats were divided into four groups (n = 8 each): rats on a normal chow diet with standard light‐dark cycle, rats on a normal chow diet with constant light exposure, rats on an HFD with standard light‐dark cycle, and rats on an HFD with constant light exposure. After 16 weeks of treatment, changes in anthropometric parameters, estrous cycle, hormone profiles, ovarian pathology, and gut microbiota and short‐/medium‐chain fatty acids in colon contents were assessed. Results Constant light exposure aggravated PCOS‐like phenotypes in HFD‐fed rats, such as hyperandrogenism, disrupted estrous cycle, and polycystic ovaries. Additionally, constant light exposure and an HFD synergized to decrease α‐diversity of gut microbiota, create a reduced abundance of Ruminococcus genus, and create an increased abundance of Firmicutes and the Firmicutes/Bacteroidetes ratio. In HFD‐fed rats, the group with constant light exposure had an increase in propionate acid and a decrease in total medium‐chain fatty acids in colon contents compared with the standard light‐dark cycle group. Conclusions Constant light exposure causes gut dysbiosis, alters production of short‐ and medium‐chain fatty acids, and aggravates PCOS‐like traits in HFD‐fed rats.

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Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome

Cited by 41 publications

References 61 publications

Decreased brain and muscle ARNT-like protein 1 expression mediated the contribution of hyperandrogenism to insulin resistance in polycystic ovary syndrome

Decreased brain and muscle ARNT-like protein 1 expression mediated the contribution of hyperandrogenism to insulin resistance in polycystic ovary syndrome

BMAL1 promotes colorectal cancer cell migration and invasion through ERK‐ and JNK‐dependent c‐Myc expression

Constant light exposure alters gut microbiota and short‐/medium‐chain fatty acids and aggravates PCOS‐like traits in HFD‐fed rats

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