Genistein regulates adipogenesis by blocking the function of adenine nucleotide translocase-2 in the mitochondria

Ikeda, Takahiro; Watanabe, Shun; Mitani, Takahiko

doi:10.1093/bbb/zbab203

Cited by 8 publications

(11 citation statements)

References 58 publications

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“…These results indicated that PHBs localized in the mitochondrial inner membrane could be involved in mitochondrial maintenance in adipocytes. Our previous study showed that genistein binds to mitochondrial proteins 31 , suggesting that genistein translocates to the mitochondria and may affect the function of mitochondrial PHB1. However, this should be veri ed in future studies.…”

Section: Discussionmentioning

confidence: 97%

“…For instance, in skeletal muscle cells, the expression of the β2-adrenergic receptor is upregulated by genistein, which is independent of ER 32 . Genistein increases adiponectin expression by inhibiting tyrosine kinases in synovial broblasts 33 and suppresses ATP synthesis by binding to the mitochondrial protein ANT2 in preadipocytes 31 . In addition, molecular docking studies have shown that genistein binds to c-Jun-NH2terminal kinase 1 (JNK1) and suppresses TNF-α-mediated downregulation of adiponectin by inhibiting the JNK1 in mature adipocytes 34 .…”

Section: Discussionmentioning

confidence: 99%

“…The preparation of iso avone-xed beads and the pull-down assay of genistein-bound proteins were previously described 31 . Bead-bound proteins were subjected to SDS-PAGE, followed by silver staining.…”

Section: Identi Cation Of Genistein-binding Proteinsmentioning

confidence: 99%

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Genistein enhances NAD+ biosynthesis by binding to prohibitin 1 and upregulating nicotinamide phosphoribosyltransferase (NAMPT) in adipocytes

Watanabe

Haruyama

Umezawa

et al. 2023

Preprint

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Decreased NAD+ levels in adipocytes cause adipose-tissue dysfunction, leading to systemic glucose and lipid metabolism failure. Therefore, developing small molecules and nutraceuticals that can increase NAD+ levels in adipocytes is necessary. Genistein, a nutraceutical derived from soybeans, has various physiological activities and improves glucose and lipid metabolism. In this study, we aimed to unravel the effects of genistein on the intracellular NAD+ levels in adipocytes and the underlying molecular mechanisms. We showed that genistein enhanced NAD+ biosynthesis by increasing the expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis. A pull-down assay using genistein-immobilized beads identified prohibitin 1 (PHB1) as a target protein of genistein. The knockdown of PHB1 suppressed the genistein-induced increase in NAMPT expression and NAD+ levels in adipocytes. Genistein-bound PHB1 contributed to the stabilization of the transcription factor CCAAT/enhancer-binding protein β through activation of extracellular signal-regulated kinase, resulting in increased NAMPT expression at the transcriptional level. Genistein induced dephosphorylation of peroxisome proliferator-activated receptor at serine 273 and increased the insulin-sensitizing adipokine, adiponectin, in adipocytes, whereas the knockdown of NAMPT and PHB1 abolished these genistein-mediated effects. Our results proved the potential efficacy of food components in promoting NAD+ levels and restoring metabolic function in adipocytes. Furthermore, we identified PHB1, localized to the plasma membrane, as a candidate target protein for increased expression of NAMPT in adipocytes. Overall, these findings will assist in developing NAD+ boosting strategies to alleviate the metabolic dysfunctions in adipose tissues.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Genistein enhances NAD+ biosynthesis by binding to prohibitin 1 and upregulating nicotinamide phosphoribosyltransferase (NAMPT) in adipocytes

Watanabe

Haruyama

Umezawa

et al. 2023

Preprint

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“…The concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) were determined by using a fluorescence detector (96-well; Promega) as previously described. 27…”

Section: Methodsmentioning

confidence: 99%

Puerarin Alleviates LPS-Induced H9C2 Cell Injury by Inducing Mitochondrial Autophagy

Chang

Luo

et al. 2022

Journal of Cardiovascular Pharmacology

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Sepsis leads to the damage of multiple organs, and thereby adversely affects the cardiovascular system. At present, no effective method has been found to treat myocardial injury caused by sepsis. Although Puerarin was reported to attenuate lipopolysaccharide (LPS)-induced mitochondrial injury in H9C2 cells, the effects of Puerarin in sepsis-induced myocardial injury remain unclear. In this study, H9C2 cells were stimulated with LPS, CCK-8 assays were performed to assess cell viability, and flow cytometry and TUNEL staining were used to assess cell apoptosis. Levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and enzyme activity were investigated using commercial kits. Reactive oxygen species (ROS) levels in H9C2 cells were detected by flow cytometry. Autophagosomes in the mitochondria of H9C2 cells were observed by transmission electron microscope, and protein expression was assessed by western blotting. Furthermore, in vivo experiments were applied to test the function of Puerarin in sepsis. We found that Puerarin significantly reversed LPS-induced decreases in H9C2 cell viability by inhibiting apoptosis. The ROS levels in H9C2 cells were significantly upregulated by LPS, but that effect was markedly reduced by Puerarin. In addition, Puerarin attenuated LPS-induced mitochondrial injury in H9C2 cells by regulating dynamin-related protein 1 (Drp1) and mitofusin 1 (MFN1). LPS decreased enzyme activity and reduced the levels of ADP, ALP, and AMP in mitochondria; however, those effects were reversed by Puerarin. Puerarin and Torin1 reversed LPSinduced inhibition of autophagy in the mitochondria of H9C2 cells via mediation of p62, LC3B, Pink1, and Parkin. Puerarin notably inhibited the progression of sepsis in vivo. Puerarin inhibited LPSinduced H9C2 cell injury by inducing mitochondrial autophagy, which acts as a mechanism for preventing myocardial injury caused by sepsis.

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“…Cell culture. Immortalized adipose stromal cells (ASCs) derived from mice were prepared and cultured as previously described (25). Confluent ASCs were induced to differentiate into adipocytes using adipocyte differentiation reagents (0.5 mm 3-isobutyl-1-methylxanthine, 10 mg/mL insulin, 1 mm cortisone, 10 mm rosiglitazone, and 8 mg/mL biotin) in Dulbecco's modified Eagle's medium (DMEM) containing 4.5 g/L glucose, 10% fetal bovine serum (FBS), 100 units/mL penicillin, and 100 mg/mL streptomycin in the presence or absence of 25VD (100 nm) for the first 2 d. The cells were then cultured in the same medium with insulin and biotin in presence or absence of 25VD (100 nm) for an additional 5 d (total 7 d).…”

Section: Methodsmentioning

confidence: 99%

25-Hydroxyvitamin D Increases Insulin-Stimulated Glucose Uptake by Enhancing Adipocyte Differentiation

Nakashima

Mitani

2022

J Nutr Sci Vitaminol

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Vitamin D and its receptor (vitamin D receptor; VDR) regulate calcium homeostasis in mammals. Recently, studies have shown that serum concentrations of 25-hydroxyvitamin D (25VD) are negatively associated with insulin resistance and the incidence of type 2 diabetes. In adipose tissues, glucose transporter 4 (GLUT4) contributes to insulin-stimulated glucose uptake; however, the effect of 25VD on glucose uptake in adipocytes remains unclear. We examined the role of 25VD in glucose uptake and the differentiation of adipose-derived stromal cells. Insulin-stimulated glucose uptake in adipocytes was increased by treatment with 25VD and decreased by VDR knockdown. The expression levels of GLUT4 were upregulated by 25VD treatment. 25VD exposure increased the expression of adipocyte differentiation-related genes including peroxisome proliferator-activated receptor g and CCAAT/enhancer-binding proteins through VDR, thereby enhancing the formation of mature adipocytes. Moreover, 25VD increased the expression levels of 11b-hydroxysteroid dehydrogenase 1 (HSD11B1), which catalyzes the conversion of cortisone to cortisol in a concentration-dependent manner. 25VD-stimulated adipocyte differentiation was suppressed by HSD11B1 knockdown. Cortisone together with 25VD enhanced adipocyte differentiation, whereas synthesized glucocorticoid dexamethasone-induced adipocyte differentiation is not promoted by 25VD. Overall, these results indicate that 25VD stimulates adipocyte differentiation through the induction of HSD11B1 expression, leading to increased insulin-induced glucose uptake in adipocytes.

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Genistein regulates adipogenesis by blocking the function of adenine nucleotide translocase-2 in the mitochondria

Cited by 8 publications

References 58 publications

Genistein enhances NAD+ biosynthesis by binding to prohibitin 1 and upregulating nicotinamide phosphoribosyltransferase (NAMPT) in adipocytes

Genistein enhances NAD+ biosynthesis by binding to prohibitin 1 and upregulating nicotinamide phosphoribosyltransferase (NAMPT) in adipocytes

Puerarin Alleviates LPS-Induced H9C2 Cell Injury by Inducing Mitochondrial Autophagy

25-Hydroxyvitamin D Increases Insulin-Stimulated Glucose Uptake by Enhancing Adipocyte Differentiation

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