A novel phosphorylation by AMP-activated kinase regulates RUNX2 from ubiquitination in osteogenesis over adipogenesis

Chava, Suresh; Chennakesavulu, S.; Gayatri, B Meher; Reddy, Aramati B. M.

doi:10.1038/s41419-018-0791-7

Cited by 54 publications

(52 citation statements)

References 52 publications

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“…This gene has been identified as upregulated in adipose-derived stromal/progenitor cells in SAT of long-term weight losing initially obese human females, in which DIRAS3 gene reduced adipogenesis and activated autophagy through the negative regulation of Akt-mTOR signalling 54 . In line with this result, genes involved in the induction of adipogenesis pathway 55 (BMP5, BMP7, CEBPA and ZNF521) were identified (either up-or down-regulated) in animals fed on western diet while genes (BMP2 and RUNX2) that favour MSCs differentiation into osteoblasts vs adipogenic commitment 56 resulted upregulated in the supplemented pigs.…”

Section: Discussionsupporting

confidence: 55%

Dietary intake of bioactive ingredients impacts liver and adipose tissue transcriptomes in a porcine model of prepubertal early obesity

Ballester

Quintanilla

Ortega

et al. 2020

Sci Rep

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Global prevalence of obesity has increased to epidemic proportions over the past 40 years, with childhood obesity reaching alarming rates. In this study, we determined changes in liver and adipose tissue transcriptomes of a porcine model for prepubertal early obesity induced by a high-calorie diet and supplemented with bioactive ingredients. A total of 43 nine-weeks-old animals distributed in four pens were fed with four different dietary treatments for 10 weeks: a conventional diet; a western-type diet; and a western-type diet with Bifidobacterium breve and rice hydrolysate, either adding or not omega-3 fatty acids. Animals fed a western-type diet increased body weight and total fat content and exhibited elevated serum concentrations of cholesterol, whereas animals supplemented with bioactive ingredients showed lower body weight gain and tended to accumulate less fat. An RNA-seq experiment was performed with a total of 20 animals (five per group). Differential expression analyses revealed an increase in lipogenesis, cholesterogenesis and inflammatory processes in animals on the western-type diet while the supplementation with bioactive ingredients induced fatty acid oxidation and cholesterol catabolism, and decreased adipogenesis and inflammation. These results reveal molecular mechanisms underlying the beneficial effects of bioactive ingredient supplementation in an obese pig model. administration of Bifidobacterium breve B-3 modified the hepatic expression of genes related to lipid metabolism and response to stress 4 . A reduction in body fat has been also observed in healthy pre-obese individuals receiving Bifidobacterium breve B-3, but no significant improvement of blood parameters was found 5 . In partial agreement, studies with rodent models of obesity have demonstrated the anti-obesity effect of n-3 polyunsaturated fatty acids (PUFA). Reduction of fat mass was predominantly observed in mice fed a HFD and supplemented with n-3 PUFA (reviewed in 6 ). However, the effects of n-3 PUFA in human obesity remain inconclusive. On the other hand, rice proteins and their hydrolysates added to high fat and/or high cholesterol diets have shown to have anti-obesity and hypocholesterolemic effects through the effective modulation of cholesterol and triglyceride metabolism, and the activity of hepatic genes related to lipid metabolism 7,8 .Overall, these experimental evidences reinforce the relevance of using bioactive dietetic supplements to prevent and treat obesity. However, as most of these studies were performed in rodent models, the underlying biological mechanisms determining anti-obesity effects are difficult to translate into humans, due to the vast differences between these species at the physiological and metabolic level 9 . In contrast, pigs are excellent models for human obesity and its comorbidities, given their similarity in terms of anatomy, physiology, metabolism, and genetics 9-11 .To date, a limited number of pig models for childhood obesity have been developed by short term (≤ 12 wk.) dietary interven...

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Section: Discussionsupporting

confidence: 55%

Dietary intake of bioactive ingredients impacts liver and adipose tissue transcriptomes in a porcine model of prepubertal early obesity

Ballester

Quintanilla

Ortega

et al. 2020

Sci Rep

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“…After overexpression of miR-505 mimics in MC3T3-E1 cells, the expression of RUNX2 was downregulated, suggesting that RUNX2 could be a target gene of miR-505. The RUNX2 gene is a landmark gene of osteogenic differentiation and bone formation [26]. RUNX2 can activate the transcription and expression of OPN, ALP, and OCN [27].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-505 is involved in the regulation of osteogenic differentiation of MC3T3-E1 cells partially by targeting RUNX2

Chen

Cai

et al. 2020

J Orthop Surg Res

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Objective: Evidence suggests that microRNAs (miRNAs) regulate the expression of genes involved in bone metabolism. This study aimed to investigate the role of miR-505 in the osteogenic differentiation of MC3T3-E1 cells. Methods: We performed miRNA sequencing to identify differentially expressed miRNAs between MC3T3-E1 cells treated with osteogenic induction medium (OIM) and control cells. Bioinformatics analysis was performed by using the TargetScan and miRDB databases. The expression of miR-505 in MC3T3-E1 cells was detected during osteogenic differentiation. After transfection with miR-505 mimic or miR-505 inhibitor, MC3T3-E1 cells were induced to differentiate into osteoblasts, and the expression of osteogenic differentiation markers (Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN), and osterix (OSX)) was detected. Results: miR-505 was the most downregulated miRNA among the differentially expressed miRNAs. The RUNX2 gene was identified as a potential target of miR-505 using the target prediction program. miR-505 expression was downregulated during osteogenic differentiation of MC3T3-E1 cells. The expression of osteogenic marker genes was inhibited in MC3T3-E1 cells after transfection with miR-505. However, the expression of osteogenic marker genes was upregulated after transfection with miR-505 inhibitor.Conclusion: This study is the first to report miR-505 could bind to the RUNX2 gene and thus regulate partly the dysfunction of osteoblasts differentiation, which is expected to be targets for the treatment of osteoporosis.

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“…GTP treatment also increased Bmp2 expression. Runx2 and Bmp2 are the critical molecular switches involved in the osteogenic differentiation of mesenchymal stem cells [26,27]. These results indicate that GTP is capable of promoting osteogenic differentiation through up-regulating the gene expression of Runx2 and Bmp2, and inhibiting adipogenic differentiation of ADSCs by down-regulating the expression of Pparγ.…”

Section: Discussionmentioning

confidence: 84%

Combating Osteoporosis and Obesity With Green Tea Polyphenols: Molecular Switching of Osteogenesis Versus Adipogenesis During Early Differentiation of Human Adipose Tissue-Derived Stem Cells

Lao¹,

Tan²,

Johnson³

et al. 2020

Preprint

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Background: Osteoporosis is a metabolic disease affecting the bone mineral density associated with increased adiposity in the aging population with obesity. The nutrients to control osteoblast and adipocyte differentiation from a common precursor, the pluripotent mesenchymal stem cell (MSC), may be a promising therapy for osteoporosis. Previously, we have shown that green tea polyphenols (GTP) exert anti-adipogenic effects on preadipocyte proliferation. In the present study, we investigated regulatory effects of GTP on osteogenesis and adipogenesis during early differentiation of human adipose tissue-derived stem cells (hADSCs). Methods: GTP at concentrations of 1 and 10 µg/ml was incubated with primary hADSCs in presence or absence of pioglitazone (100 µmol) during hADSCs differentiation. Adipogenesis of hADSCs was determined by Oil Red O staining and measurement of the cellular triglyceride synthesis in mature adipocyte. Alkaline phosphatase (ALP) assay and the measurement of intracellular calcium were utilized to determine osteoporosis of hADSCs. Immunofluorescence staining and qRT-PCR were employed to detect PPARγ-CEBPA regulated adipogenic pathway and the RUNX2-BMP2 mediated osteogenic pathway. Results: GTP treatment significantly decreased lipid accumulation and the cellular triglyceride synthesis in mature adipocytes and attenuated pioglitazone-induced adipogenesis in a dose-dependent manner. GTP downregulated protein and mRNA expression of Pparγ and attenuated pioglitazone-stimulated Cebpa expression in mature adipocytes. Concurrently, measurements of calcium content and ALP activity showed that GTP treatment significantly enhanced hADSCs differentiation into osteocytes compared with the control and pioglitazone-treated cells. Meanwhile, GTP upregulated protein and mRNA expression of RunX2 and Bmp2 compared to the control and GTP at 10 µg/mL significantly attenuated the decreased mRNA expression of Runx2 and Bmp2 by pioglitazone. Conclusions: The present study demonstrated that GTP possess a greater ability to facilitate osteogenesis and simultaneously inhibit hADSCs differentiation into the adipogenic lineage through upregulating the RUNX2-BMP2 mediated osteogenic pathway and suppressing PPARγ-induced signaling of adipogenesis. The findings of this study highlight that GTP may be a therapeutic intervention to combat osteoporosis associated obesity.

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A novel phosphorylation by AMP-activated kinase regulates RUNX2 from ubiquitination in osteogenesis over adipogenesis

Cited by 54 publications

References 52 publications

Dietary intake of bioactive ingredients impacts liver and adipose tissue transcriptomes in a porcine model of prepubertal early obesity

Dietary intake of bioactive ingredients impacts liver and adipose tissue transcriptomes in a porcine model of prepubertal early obesity

MicroRNA-505 is involved in the regulation of osteogenic differentiation of MC3T3-E1 cells partially by targeting RUNX2

Combating Osteoporosis and Obesity With Green Tea Polyphenols: Molecular Switching of Osteogenesis Versus Adipogenesis During Early Differentiation of Human Adipose Tissue-Derived Stem Cells

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