Theobromine enhances the conversion of white adipocytes into beige adipocytes in a PPARγ activation-dependent manner

Tanaka, Eijirou; Mitani, Takahiko; Nakashima, Momona; Yonemoto, Eito; Fujii, Hiroshi; Ashida, Hitoshi

doi:10.1016/j.jnutbio.2021.108898

Cited by 22 publications

(11 citation statements)

References 52 publications

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“…In addition, PRDM16 and PGC1a have been reported to be transcriptional regulatory factors that regulate the formation of brown and beige adipocytes in mature white adipocytes. PRDM16 induces the differentiation of white adipocytes into brown adipocytes and induces the expression of its partner PGC1a, which subsequently induces an increase in UCP-1 expression [ 10 , 12 , 29 ]. RT-qPCR and Western blotting analyses were performed to measure the expression levels of PRDM16 and PGC1a, which regulate the expression of the thermogenic gene UCP-1.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, mitochondrial biosynthesis is the process of generating new mitochondria, and PGC-1a is a key regulator of mitochondrial biosynthesis that can activate the expression of downstream mitochondrial factors, including UCP-1, in various signaling pathways. Brown adipocytes also induce the expression of native UCP-1 in the inner mitochondrial membrane [ 10 , 12 , 27 ]. To confirm the effect of Cu B, Cu E, and Cu I on mitochondrial biosynthesis, the mitochondrial mass was measured using a confocal microscope after staining with MitoTracker.…”

Section: Resultsmentioning

confidence: 99%

“…Beige adipocytes due to browning have a relatively large number of mitochondria compared to white adipocytes and are colored brown by the cytochrome pigment present in the mitochondria. Beige adipocytes also undergo the process of optimizing fat breakdown to provide fuel for heat production [ 8 , 10 ]. The expression of UCP-1 in adipocytes with multivesicular lipid droplets, including the ability to generate heat, is termed as beige adipocytes.…”

Section: Introductionmentioning

confidence: 99%

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Cucurbitacin B-, E-, and I-Induced Browning of White Adipocytes Is Promoted by the Inhibition of Phospholipase D2

Park

Kang

et al. 2022

IJMS

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The mechanism of white adipose tissue browning is not well understood; however, naturally occurring compounds are known to play a positive role. The effects of cucurbitacins B, E, and I on the browning of mature white adipocytes were investigated. First, the cell viability exhibited by cucurbitacins B, E, and I in pre- and mature adipocytes was verified. Cucurbitacins B, E, and I had no effect on cell viability in pre- and mature adipocytes at concentrations up to 300 nM. To investigate the characteristics of representative beige adipocytes, the formation and morphology of cucurbitacin B, E, and I lipid droplets were verified. The total lipid droplet surface area, maximum Feret diameter, and total Nile red staining intensity of cucurbitacin B-, E-, and I-treated adipocytes were lower than those of mature white adipocytes. Furthermore, treatment of white mature adipocytes with cucurbitacin B, E, and I led to the formation of several small lipid droplets that are readily available for energy expenditure. We evaluated the effect of cucurbitacins B, E, and I on the expression of representative browning markers UCP1, PGC1a, and PRDM16, which participate in the browning of white adipose tissue. Cucurbitacins B, E, and I increased the mRNA and protein expression levels of UCP1, PGC1a, and PRDM16 in a concentration-dependent manner. To promote energy consumption by beige adipocytes, active mitochondrial biogenesis is essential. Next, we investigated the effects of cucurbitacin B, E, and I on mitochondrial biogenesis in mature adipocytes. Mitochondrial mass increased when mature adipocytes were treated with cucurbitacin B, E, and I. The degree of cucurbitacin B-, E- and I-induced transformation of white adipocytes into beige adipocytes was in the order of Cu E > Cu B > Cu I. To verify the effect of phospholipase D2 on the browning of white adipocytes, CAY10594—a PLD2 pharmacological inhibitor, and a knockdown system were used. PLD2 inhibition and knockdown improved the expression levels of UCP1, PGC1a, and PRDM16. In addition, PLD2 inhibition and knockdown in mature white adipocytes promoted mitochondrial biosynthesis. The effect of PLD2 inhibition and knockdown on promoting browning of white adipocytes significantly increased when Cu B, Cu E, and Cu I were co-treated. These data indicate that mature white adipocytes’ beige properties were induced by cucurbitacins B, E, and I. These effects became more potent by the inhibition of PLD2. These findings provide a model for determining anti-obesity agents that induce browning and increase energy expenditure in mature white adipocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cucurbitacin B-, E-, and I-Induced Browning of White Adipocytes Is Promoted by the Inhibition of Phospholipase D2

Park

Kang

et al. 2022

IJMS

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“…Immuno uorescence analysis was performed as previously described 57 . Brie y, 3T3-L1 cells were transfected with the Myc-PHB1 expression vector.…”

Section: Immuno Microscopymentioning

confidence: 99%

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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“…After 40 h of stimulation, the cells were harvested and the activities of firefly and Renilla luciferase were measured in the same cell lysate using the Dual-Luciferase Reporter Assay System (Promega) and GloMax Luminometer (Promega). Relative NF-κB promoter activities were calculated as the ratio of NF-κB-Luc to SV40-Luc (C2C12 cells) or CMV-Luc (A10 cells)[30,39].2.5. Immunocytochemistry C2C12 cells were fixed with 2% paraformaldehyde, permeabilized with 0.2% Triton X-100 (Nacalai), and immunostained with rabbit polyclonal anti-NF-κB p65 subunit antibody (ab16502; Abcam, Cambridge, UK) or rabbit polyclonal anti-β-catenin antibody (#9562; Cell Signaling Technology, Danvers, MA, USA).…”

mentioning

confidence: 99%

Anti-nucleolin aptamer, iSN04, inhibits the inflammatory responses in myoblasts by modulating the β-catenin/NF-κB signaling pathway

Yamamoto

Miyoshi

Morioka

et al. 2023

Preprint

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A myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to be a nucleic acid drug for the muscle wasting associated with chronic diseases. The present study investigated the anti-inflammatory mechanism of iSN04 in the murine myoblast cell line C2C12. Tumor necrosis factor-α (TNF-α) or Toll-like receptor (TLR) ligands (Pam3CSK4 and FSL-1) induced nuclear translocation and transcriptional activity of nuclear factor-κB (NF-κB), resulting in upregulated expression of TNF-α and interleukin-6. Pre-treatment with iSN04 significantly suppressed these inflammatory responses by inhibiting the nuclear accumulation of β-catenin induced by TNF-α or TLR ligands. These results demonstrate that antagonizing nucleolin with iSN04 downregulates the inflammatory effect mediated by the β-catenin/NF-κB signaling pathway in myoblasts. In addition, the anti-inflammatory effects of iSN04 were also observed in smooth muscle cells and pre-adipocytes, suggesting that iSN04 may be useful in preventing inflammation induced by metabolic disorders.

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Theobromine enhances the conversion of white adipocytes into beige adipocytes in a PPARγ activation-dependent manner

Cited by 22 publications

References 52 publications

Cucurbitacin B-, E-, and I-Induced Browning of White Adipocytes Is Promoted by the Inhibition of Phospholipase D2

Cucurbitacin B-, E-, and I-Induced Browning of White Adipocytes Is Promoted by the Inhibition of Phospholipase D2

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

Anti-nucleolin aptamer, iSN04, inhibits the inflammatory responses in myoblasts by modulating the β-catenin/NF-κB signaling pathway

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