Acetylation of Histone and Modification of Gene Expression via HDAC Inhibitors Affects the Obesity

Obesity is due to imbalance between energy intake and energy expenditure. Adipose tissues are the main site for the fat storage as well as for dissipation. There are two types of adipose tissues: white adipose tissue, which store fat as triglyceride, brown adipose tissue, which burns the fat into energy through the thermogenesis due to uncoupling protein1 present in inner mitochondrial membrane. Histone acylation causes changes in the chromatin structure without causing any change in the deoxyribonucleic acidsequence and thus regulate gene expression.Histonedeacetylase causes the deacylation of histone and interfere with function of histone. Thus histonedeacetylase inhibitors alter the expression of thermogenic gene encoding uncoupling protein 1, peroxisome proliferator activated receptor γ and also causes browning or beiging of white adipose tissue and increases the energy expenditure.

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Current Progress in Adipose Tissue Biology: Implications in Obesity and Its Comorbidities

The Indonesian Biomedical Journal ◽

10.18585/inabj.v12i2.1171 ◽

2020 ◽

Vol 12 (2) ◽

pp. 85-101

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Common Factor ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Brown Adipose ◽

Key Factor ◽

Beige Fat

BACKGROUND: Obesity has been decades become a highly interest study, accompanied by the realization that adipose tissue (AT) plays a major role in the regulation of metabolic function.CONTENT: In past few years, adipocytes classification, development, and differentiation has been significant changes. The white adipose tissue (WAT) can transform to a phenotype like brown adipose (BAT) type and function. Exercise and cold induction were the most common factor for fat browning; however batokines such as fibroblast growth factor (FGF)-21, interleukin (IL)-6, Slit homolog 2 protein (SLIT2)-C, and Meteorin-like protein (METRNL) perform a beneficial browning action by increasing peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α protein levels, a key factor to stimulate mitochondrial biogenesis and uncoupling Protein 1 (UCP1) transcription, thus change the WAT phenotype into beige.SUMMARY: AT recently known as a complex organ, not only bearing a storage function but as well as the master regulator of energy balance and nutritional homeostasis; brown and beige fat express constitutively high levels of thermogenic genes and raise our expectation on new strategies for fighting obesity and metabolic disorders.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, inflammation, IR, metabolic disease

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Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Cells ◽

10.3390/cells8080831 ◽

2019 ◽

Vol 8 (8) ◽

pp. 831 ◽

Cited By ~ 1

Author(s):

Virag Vas ◽

Tamás Háhner ◽

Gyöngyi Kudlik ◽

Dávid Ernszt ◽

Krisztián Kvell ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Growth Factor Receptor ◽

Cellular Level ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Kinase Substrate ◽

Downstream Signaling ◽

Brown Adipose ◽

Morphological Differences

Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.

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Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression

Endocrinology ◽

10.1210/en.2011-1339 ◽

2012 ◽

Vol 153 (1) ◽

pp. 113-122 ◽

Cited By ~ 23

Author(s):

Shoba Shetty ◽

Maria A. Ramos-Roman ◽

You-Ree Cho ◽

Jonathan Brown ◽

Jorge Plutzky ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Free Fatty Acid ◽

Uncoupling Protein ◽

Retinol Binding Protein ◽

Peroxisome Proliferator ◽

Tissue Mass ◽

Triglyceride Synthesis ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

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Trans-10, cis-12 conjugated linoleic acid causes inflammation and delipidation of white adipose tissue in mice: a microarray and histological analysis

Physiological Genomics ◽

10.1152/physiolgenomics.00076.2006 ◽

2006 ◽

Vol 27 (3) ◽

pp. 282-294 ◽

Cited By ~ 71

Author(s):

P. Christopher LaRosa ◽

Jess Miner ◽

Yuannan Xia ◽

You Zhou ◽

Steve Kachman ◽

...

Keyword(s):

Adipose Tissue ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

White Adipose Tissue ◽

Binding Protein ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Functional Responses ◽

Peroxisome Proliferator Activated Receptor ◽

Transcript Levels

A combined histological and microarray analysis of the white adipose tissue (WAT) of mice fed trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) was performed to better define functional responses. Mice fed t10c12 CLA for 14 days lost 85% of WAT mass, 95% of adipocyte lipid droplet volume, and 15 or 47% of the number of adipocytes and total cells, respectively. Microarray profiling of replicated pools ( n = 2 per day × diet) of control and treated mice ( n = 140) at seven time points after 1–17 days of t10c12 CLA feeding found between 2,682 and 4,216 transcript levels changed by twofold or more. Transcript levels for genes involved in glucose and fatty acid import or biosynthesis were significantly reduced. Highly expressed transcripts for lipases were significantly reduced but still abundant. Increased levels of mRNAs for two key thermogenesis proteins, uncoupling protein 1 and carnitine palmitoyltransferase 1, may have increased energy expenditures. Significant reductions of mRNAs for major adipocyte regulatory factors, including peroxisome proliferator activated receptor-γ, sterol regulatory binding protein 1, CAAT/enhancer binding protein-α, and lipin 1 were correlated with the reduced transcript levels for key metabolic pathways in the WAT. A prolific inflammation response was indicated by the 2- to 100-fold induction of many cytokine transcripts, including those for IL-6, IL-1β, TNF ligands, and CXC family members, and an increased density of macrophages. The mRNA changes suggest that a combination of cell loss, increased energy expenditure, and residual transport of lipids out of the adipocytes may account for the cumulative mass loss observed.

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Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1519358112 ◽

2015 ◽

Vol 112 (45) ◽

pp. 14006-14011 ◽

Cited By ~ 22

Author(s):

Yifei Miao ◽

Wanfu Wu ◽

Yubing Dai ◽

Laure Maneix ◽

Bo Huang ◽

...

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Energy Expenditure ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Thyroid Stimulating Hormone ◽

Vital Role ◽

Normal Diet ◽

Subcutaneous White Adipose Tissue ◽

Brown Adipose

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

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

Molecules ◽

10.3390/molecules25245954 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5954

Author(s):

Kyeong Jo Kim ◽

Eui-Seon Jeong ◽

Ki Hoon Lee ◽

Ju-Ryun Na ◽

Soyi Park ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Ellagic Acid ◽

Uncoupling Protein ◽

Hormone Sensitive Lipase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Rubus Coreanus ◽

Associated Proteins

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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Lipocalin 2 regulates retinoic acid-induced activation of beige adipocytes

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0017 ◽

2018 ◽

Vol 61 (3) ◽

pp. 115-126 ◽

Cited By ~ 2

Author(s):

Jessica A Deis ◽

Hong Guo ◽

Yingjie Wu ◽

Chengyu Liu ◽

David A Bernlohr ◽

...

Keyword(s):

Adipose Tissue ◽

Retinoic Acid ◽

Uncoupling Protein ◽

Oxidative Capacity ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Lipocalin 2 ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Beige Adipocytes

Lipocalin-2 (LCN2) has been previously characterized as an adipokine regulating thermogenic activation of brown adipose tissue and retinoic acid (RA)-induced thermogenesis in mice. The objective of this study was to explore the role and mechanism for LCN2 in the recruitment and retinoic acid-induced activation of brown-like or ‘beige’ adipocytes. We found LCN2 deficiency reduces key markers of thermogenesis including uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in inguinal white adipose tissue (iWAT) and inguinal adipocytes derived from Lcn2 −/− mice. Lcn2 −/− inguinal adipocytes have attenuated insulin-induced upregulation of thermogenic gene expression and p38 mitogen-activated protein kinase (p38MAPK) signaling pathway activation. This is accompanied by a lower basal and maximal oxidative capacity in Lcn2 −/− inguinal adipocytes, indicating mitochondrial dysfunction. Recombinant Lcn2 was able to restore insulin-induced p38MAPK phosphorylation in both WT and Lcn2 −/− inguinal adipocytes. Rosiglitazone treatment during differentiation of Lcn2 −/− adipocytes is able to recruit beige adipocytes at a normal level, however, further activation of beige adipocytes by insulin and RA is impaired in the absence of LCN2. Further, the synergistic effect of insulin and RA on UCP1 and PGC-1α expression is markedly reduced in Lcn2 −/− inguinal adipocytes. Most intriguingly, LCN2 and the retinoic acid receptor-alpha (RAR-α) are concurrently translocated to the plasma membrane of adipocytes in response to insulin, and this insulin-induced RAR-α translocation is absent in adipocytes deficient in LCN2. Our data suggest a novel LCN2-mediated pathway by which RA and insulin synergistically regulates activation of beige adipocytes via a non-genomic pathway of RA action.

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Photoperiodic regulation of gene expression in brown and white adipose tissue of Siberian hamsters (Phodopus sungorus)

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2002.282.1.r114 ◽

2002 ◽

Vol 282 (1) ◽

pp. R114-R121 ◽

Cited By ~ 23

Author(s):

Gregory E. Demas ◽

Robert R. Bowers ◽

Timothy J. Bartness ◽

Thomas W. Gettys

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Regulation Of Gene Expression ◽

Ribonuclease Protection Assay ◽

Peroxisome Proliferator ◽

Uncoupling Protein 1 ◽

Siberian Hamsters ◽

Brown Adipose

Siberian hamsters exhibit seasonal fluctuations in white adipose tissue (WAT) mass, with peaks in long “summerlike” days (LDs) and nadirs in short “winterlike” days (SDs). These responses can be mimicked in the laboratory after transfer from LDs to SDs. The purpose of the present study was to test whether changes in WAT and brown adipose tissue (BAT) gene expression that are mediated by the sympathetic nervous system in other obesity models are also associated with seasonal adiposity changes in Siberian hamsters. SDs decreased WAT mass and leptin mRNA, increased WAT β3-adrenoceptor mRNA, and induced retroperitoneal WAT uncoupling protein-1 mRNA (the latter measured by RT-PCR, others measured by ribonuclease protection assay) while increasing BAT uncoupling protein-1 and peroxisome proliferator-activated receptor-γ coactivator-1 mRNAs. These effects were not due to SD-induced gonadal regression and largely occurred before the usual SD-induced decreases in food intake. Thus the SD-induced decreased adiposity of Siberian hamsters may be due to a coordinated suite of WAT and BAT gene transcription changes ultimately increasing lipid mobilization and utilization.

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The Effects of Royal Jelly and Tocotrienol Rich Fraction Along with Calorie Restriction Diet on White Fat Browning and Brown Adipocytes Activation in Obese Rats

10.21203/rs.3.rs-34722/v1 ◽

2020 ◽

Author(s):

Pardis Irandoost ◽

Naimeh Mesri Alamdari ◽

Atoosa Saidpour ◽

Farzad Shidfar ◽

Neda Roshanravan ◽

...

Keyword(s):

Adipose Tissue ◽

Calorie Restriction ◽

Royal Jelly ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Beige Adipocytes ◽

Restriction Diet ◽

Tocotrienol Rich Fraction

Abstract Background: Obesity is a public health problem across the world. Development of beige adipocytes in white adipose tissue (WAT) and activation of brown adipose tissue (BAT) can support obesity management. We aimed to investigate the effects of royal jelly (RJ) and tocotrienol-rich fraction (TRF) along with calorie restriction diet (CRD) on the genes involved in beige fat formation and BAT activation.Methods: Fifty 3-week-old male Wistar rats were fed high-fat diet (HFD) for 17 weeks. When obesity was induced, they were randomly divided into 5 groups (n=10/group): HFD, CRD, RJ+CRD, TRF+CRD, RJ+TRF+CRD for an additional 8 weeks. Finally, body weight was measured. Moreover, WAT and BAT were dissected for assessing the expression of major genes involved in adipose thermogenesis and histological changes evaluation. Results: At the end of the intervention, weight significantly decreased in RJ and RJ+TRF groups relative to the CRD group (p<0.05). RJ remarkably increased the expression of uncoupling protein 1 (UCP1) by 5.81 and 4.99 times more than CRD alone in WAT and BAT respectively (p<0.001). Expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1-α), peroxisome proliferator-activated receptor-α (PPAR-α) and Sirtuin1 (SIRT1) was significantly increased in WAT and BAT of rats receiving RJ and RJ+TRF. Peroxisome proliferator-activated receptor-γ (PPAR-Ƴ) expression was not noticeably changed in assessed adipose tissues. Brown-like adipocytes in WAT and denser adipocytes in BAT were obvious in RJ and RJ+TRF groups. However, the effect of TRF on studied genes was not noticeable. Conclusion: RJ+CRD improved markers of adipose thermogenesis and induced anti-obesity effects more than CRD alone did. Furthermore, RJ remodeled adipose tissue and could be considered as a new therapeutic target.

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Repeated Oral Administration of Flavan-3-ols Induces Browning in Mice Adipose Tissues Through Sympathetic Nerve Activation

10.20944/preprints202109.0268.v1 ◽

2021 ◽

Author(s):

Yuko Ishii ◽

Orie Muta ◽

Tomohiro Teshima ◽

Nayuta Hirasima ◽

Minayu Odaka ◽

...

Keyword(s):

Uncoupling Protein ◽

Transmembrane Protein ◽

Repeated Administration ◽

Peroxisome Proliferator ◽

Adipose Tissues ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Sympathetic Nerve Activation ◽

Pr Domain ◽

The Impact

We previously found increases in uncoupling protein (Ucp)-1 transcription in brown adipose tissue (BAT) of mice following a single oral dose of flavan 3-ols (FL), a fraction of catechins and procyanidins. It was confirmed that these changes were totally reduced by co-treatment of adrenaline blockers. According to these previous results, FL possibly activates sympathetic nervous system (SNS). In this study, we confirmed the marked increase in urinary catecholamine (CA) s projecting SNS activity following a single dose of 50 mg/kg FL. In addition, we examined the impact of the repeated administration of 50 mg/kg FL for 14 days on adipose tissues in mice. In BAT, FL tended to increase the level of Ucp-1 along with thermogenic transcriptome factors, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR domain-containing (PRDM)1. Transcription of browning markers, such as CD137 and transmembrane protein (TMEM) 26 in addition to PGC-1α were increased in epididymal adipose (eWAT) by FL. A multilocular morphology with cell size reduction was shown in the inguinal adipose (iWAT), together with increasing the level of Ucp-1 following administration of FL. These results suggest that FL produces browning in adipose through activation of the SNS.

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