Ellagic acid promotes browning of white adipose tissues in high-fat diet-induced obesity in rats through suppressing white adipocyte maintaining genes

Wang, Lifeng; Wei, Yuanyuan; Ning, Chao; Zhang, Minfang; Ping, Fan; Lei, Dongyu; Du, Jing; Gale, Mengke; Ma, Yun; Yang, Yi‐Ning

doi:10.1507/endocrj.ej18-0467

Cited by 35 publications

(24 citation statements)

References 40 publications

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“…Thus, compounds inducing UCP1 in WAT may be useful therapeutic agents for the treatment of obesity. Interestingly, the administration of ellagic acid to cold-exposed mice and HFD-fed mice induced the browning of WAT, as confirmed by the increase in UCP1 expression [52,53]. In the present study, we confirmed that an intake of 5-uRCK and its main active compound ellagic acid reduced the size of adipocytes and enhanced the production of UCP1 and PGC1α in subcutaneous ingWAT by immunoblot analyses.…”

Section: Discussionsupporting

confidence: 83%

Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo

et al. 2020

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Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.

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Section: Discussionsupporting

confidence: 83%

Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo

et al. 2020

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“…Porcine beige adipogenesis-related DEGs were screened, and the pathways of brown fat differentiation and oxidative phosphorylation were found to be enriched. Consistently, previously defined BAT/beige adipocyte markers in humans and rodents, including EBF2 [ 29 ], TNF receptor superfamily member 9 (CD137) [ 8 , 30 ], mitochondrial transcription factor A (TFAM) [ 31 , 32 ], PPARG coactivator 1 alpha (PPARGC1A) [ 33 ], type 2 iodothyronine deiodinase (DIO2) [ 34 , 35 ], and potassium channel K3 (KCNK3) [ 10 ], were indeed specifically upregulated in porcine beige adipocytes. Therefore, these well-known thermogenic genes in humans and rodents can unambiguously evaluate the thermogenic capacity of porcine adipocytes.…”

Section: Discussionsupporting

confidence: 62%

Functional and Genetic Characterization of Porcine Beige Adipocytes

Cao

Chen

et al. 2022

Cells

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Beige adipocytes are a distinct type of fat cells with a thermogenic activity that have gained substantial attention as an alternative cellular anti-obesity target in humans. These cells may provide an alternative strategy for the genetic selection of pigs with reduced fat deposition. Despite the presence of beige adipocytes in piglets, the molecular signatures of porcine beige adipocytes remain unclear. Here, white and beige adipocytes from Tibetan piglets were primarily cultured and differentiated. Compared to the white adipocytes, the beige adipocytes exhibited a stronger thermogenic capacity. RNA-sequencing-based genome-wide comparative analyses revealed distinct gene expression profiles for white and beige adipocytes. In addition, two genes, integrin alpha-2 (ITGA2) and calponin 1 (CNN1), which were specifically differentially expressed in porcine beige adipocytes, were further functionally characterized using a loss-of-function approach. Our data showed that both genes were involved in differentiation and thermogenesis of porcine beige adipocytes. Collectively, these data furthered our understanding of gene expression in porcine white and beige adipocytes. Elucidating the genetic basis of beige adipogenesis in pigs will pave the way for molecular design breeding in both pigs and large animal models of human diseases.

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“…While the loss of ALDHs coincides with complete loss of glucose utilization in both KO clones, the causal effect, if any, between these two events will need further investigation. Future studies will be needed to confirm if LDHA/B inhibitors could be combined with ALDH inhibitors to evoke a more significant chemotherapeutic effect of drugs and radiation (48), and could be explored with ALDH inhibitors such as (-)epigallocatechin gallate (65,66), rocaglamide A (67), NCT-501 (67), and ellagic acid (68).…”

Section: Reduction In Aldehyde Dehydrogenase Transcripts (Aldhs)mentioning

confidence: 99%

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Mazzio

Badisa

Mack

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Nearly all mammalian tumors of diverse tissues are believed to be dependent on fermentative glycolysis, marked by elevated production of lactic acid and expression of glycolytic enzymes, most notably lactic acid dehydrogenase (LDH). Therefore, there has been significant interest in developing chemotherapy drugs that selectively target various isoforms of the LDH enzyme. However, considerable questions remain as to the consequences of biological ablation of LDH or upstream targeting of the glycolytic pathway. Materials and Methods: In this study, we explore the biochemical and whole transcriptomic effects of CRISPR-Cas9 gene knockout (KO) of lactate dehydrogenases A and B [LDHA/B double KO (DKO)] and glucose-6-phosphate isomerase (GPI KO) in the human colon cancer cell line LS174T, using Affymetrix 2.1 ST arrays. Results: The metabolic biochemical profiles corroborate that relative to wild type (WT), LDHA/B DKO produced no lactic acid, (GPI KO) produced minimal lactic acid and both KOs displayed higher mitochondrial respiration, and minimal use of glucose with no loss of cell viability. These findings show a high biochemical energy efficiency as measured by ATP in glycolysis-null cells. Next, transcriptomic analysis conducted on 48,226 mRNA transcripts reflect 273 differentially expressed genes (DEGS) in the GPI KO clone set, 193 DEGS in the LDHA/B DKO clone set with 47 DEGs common to both KO clones. Glycolytic-null cells reflect up-regulation in gene transcripts typically associated with nutrient deprivation / fasting and possible use of fats for energy: thioredoxin interacting protein (TXNIP), mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), PPARγ coactivator 1α (PGC-1α), and acetyl-CoA acyltransferase 2 (ACAA2). Other changes in non-ergometric transcripts in both KOs show losses in "stemness", WNT signaling pathway, chemo/radiation resistance, retinoic acid synthesis, drug detoxification, androgen/estrogen activation, and extracellular matrix reprogramming genes. Conclusion: These findings demonstrate that: 1) The "Warburg effect" is dispensable, 2) loss of the LDHAB gene is not only inconsequential to viability but fosters greater mitochondrial energy, and 3) drugs that target LDHA/B are likely to be ineffective without a plausible combination second drug target. Common features across diverse mammalian tumors include the rapid glycolytic activity, greater expression of lactate dehydrogenases (LDH) and subsequent overproduction of lactic acid, occurring regardless of the presence of oxygen (Warburg effect) (1,2). This unique trait of cancer has been studied for decades, where researchers have geared off original focus from its role in metabolism to its role in acidification of the tumor microenvironment (TME), a formidable driving force for tumor growth, metastasis, aggressiveness, chemo/radiation resistance and loss of immune surveillance (3-8). This loss of immune surveillance 469 This article is freely accessible online.

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Ellagic acid promotes browning of white adipose tissues in high-fat diet-induced obesity in rats through suppressing white adipocyte maintaining genes

Cited by 35 publications

References 40 publications

Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo

Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo

Functional and Genetic Characterization of Porcine Beige Adipocytes

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

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