Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms

Fernandez‐Twinn, Denise S.; Alfaradhi, Maria Z.; Martin-Gronert, Malgorzata S.; Duque-Guimarães, Daniella E.; Piekarz, Ana; Ferland-McCollough, David; Bushell, Martin; Ozanne, Susan E.

doi:10.1016/j.molmet.2014.01.007

Cited by 102 publications

(123 citation statements)

References 46 publications

(42 reference statements)

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“…This targeting association has also been reported in colon cancer cells and adipocytes (22,23). Furthermore, it has been demonstrated that insulin-like growth factor-I receptor signaling contributes to the development of endometrial hyperplasia, the precursor to EC (24), and that IRS1 is a key mediator in oncogenic insulin-like growth factor signaling (25).…”

Section: Discussionsupporting

confidence: 68%

MicroRNA-126 inhibits the migration and invasion of endometrial cancer cells by targeting insulin receptor substrate 1

Zhao

Zhu

et al. 2015

Oncology Letters

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Abstract. MicroRNAs (miRs) have been demonstrated to serve important roles in the development and progression of human cancer, primarily through the direct targeting of oncogenes or tumor suppressors. It has been previously suggested that miR-126 may be associated with endometrial cancer (EC). However, the exact role of miR-126 in the migration and invasion of EC cells has not yet been studied. The present study demonstrated that the expression of miR-126 was significantly decreased in EC tissues when compared with matched normal adjacent tissues. The current study reverse transcriptionquantitative polymerase chain reaction was performed in order to examine the expression level of miR-126. Wound healing and transwell assays were used to examine cell migration and invasion. A luciferase reporter assay was used to determine the targeting relationship and western blotting assay was performed to detect the protein expression. Furthermore, the overexpression of miR-126 significantly inhibited EC SKOV3 cell migration and invasion. Molecular mechanism investigation established that insulin receptor substrate 1 (IRS1) functioned as a direct miR-126 target, and its expression was negatively regulated by miR-126 at a post-transcriptional level in the SKOV3 cells. Additionally, the overexpression of IRS1 reversed the inhibitory effect of miR-126 overexpression on SKOV3 cell migration and invasion. In conclusion, the current study demonstrated that miR-126 inhibited EC cell migration and invasion, at least partially through the direct targeting of IRS1, suggesting that miR-126 may aid the treatment of EC metastasis.

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Section: Discussionsupporting

confidence: 68%

MicroRNA-126 inhibits the migration and invasion of endometrial cancer cells by targeting insulin receptor substrate 1

Zhao

Zhu

et al. 2015

Oncology Letters

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“…Large fold changes were also observed at miRNAs known to be involved in metabolism. miR-126, a negative regulator of insulin signaling previously shown to be responsive to diet-induced maternal obesity in offspring adipose tissue was upregulated by 2.5-fold: 22 our data implies that diet also impacts directly on miR-126 expression in the heart.…”

Section: Discussionsupporting

confidence: 59%

Nutrition has a pervasive impact on cardiac microRNA expression in isogenic mice

et al. 2016

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The complex interaction between obesity, Western-style diets, and cardiovascular disease is of increasing interest, with a growing number of children being born to obese parents with poor lifestyle choices. These offspring have themselves an increased susceptibility to obesity and subsequent cardiovascular disease in adult life, which may be 'programmed' by their intrauterine environment. Cardiac microRNAs (miRNAs) are affected by multiple disease states, and have also been shown to be capable of exerting a hormone-like control on whole body metabolism. Here we sought to determine the effect of prenatal exposure to maternal obesity and/or postnatal exposure to a Western diet on miRNA expression in the heart. Unbiased small RNA sequencing was carried out on cardiac tissue from young adult mice born to lean or obese mothers; offspring were weaned onto either a low-fat control diet or a high-fat Western-style diet. We found 8 cardiac miRNAs that were significantly altered in response to maternal obesity, but only when the offspring were challenged postnatally with the Western diet. In contrast, postnatal exposure to the diet alone induced significant changes to the expression of a much larger number of miRNAs (33 in offspring of lean and 46 in offspring of obese). Many of the affected miRNAs have previously been implicated in various cardiac pathologies. The pervasive cardiac miRNA changes induced by a Western diet suggest that an individual's lifestyle choices outweigh the impact of any programming effects by maternal obesity on miRNA-related cardiac health.

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“…The model of maternal diet-induced obesity used here has been described previously (20). Briefly, female C57BL/6J mice were fed ad libitum a standard control chow diet (2.56 kcal/g; fat, 7.42% [kcal]; RM1, Special Diet Services) or a highly palatable energy-rich obesogenic diet (6.79 kcal/g; fat, 45% [kcal]; 45% AFE Fat, Special Diet Services) and sweetened condensed milk (55% simple sugar, 8% fat, 8% protein [wt/wt]; Nestle, fortified with mineral and vitamin mix AIN93G) from 4 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

“…Molecular analyses that have adopted a candidate approach have demonstrated that diet-induced obesity during pregnancy can lead to programmed effects on mRNA, micro RNA (miRNA), and protein expression in adipose tissue. These include studies that have shown significant reduction in expression of glucose transporter type 4 in adipose tissue, which can selectively cause insulin resistance (19), and our own studies, which demonstrate up-regulation of miR-126 that can directly influence insulin receptor substrate-1 protein expression (20). …”

mentioning

confidence: 99%

Maternal Obesity in Pregnancy Developmentally Programs Adipose Tissue Inflammation in Young, Lean Male Mice Offspring

et al. 2016

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Obesity during pregnancy has a long-term effect on the health of the offspring including risk of developing the metabolic syndrome. Using a mouse model of maternal diet-induced obesity, we employed a genome-wide approach to investigate the microRNA (miRNA) and miRNA transcription profile in adipose tissue to understand mechanisms through which this occurs. Male offspring of diet-induced obese mothers, fed a control diet from weaning, showed no differences in body weight or adiposity at 8 weeks of age. However, offspring from the obese dams had up-regulated cytokine (Tnfα; P < .05) and chemokine (Ccl2 and Ccl7; P < .05) signaling in their adipose tissue. This was accompanied by reduced expression of miR-706, which we showed can directly regulate translation of the inflammatory proteins IL-33 (41% up-regulated; P < .05) and calcium/calmodulin-dependent protein kinase 1D (30% up-regulated; P < .01). We conclude that exposure to obesity during development primes an inflammatory environment in adipose tissue that is independent of offspring adiposity. Programming of adipose tissue miRNAs that regulate expression of inflammatory signaling molecules may be a contributing mechanism.

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Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms

Cited by 102 publications

References 46 publications

MicroRNA-126 inhibits the migration and invasion of endometrial cancer cells by targeting insulin receptor substrate 1

MicroRNA-126 inhibits the migration and invasion of endometrial cancer cells by targeting insulin receptor substrate 1

Nutrition has a pervasive impact on cardiac microRNA expression in isogenic mice

Maternal Obesity in Pregnancy Developmentally Programs Adipose Tissue Inflammation in Young, Lean Male Mice Offspring

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