Nicotine induces a dual effect on the beige-like phenotype in adipocytes

Nicotine, the main component of cigarette smoke, affects white/brown adipocytes. Few studies have concentrated on beige adipocytes. In this study, 3T3-L1 cells were differentiated in the presence of nicotine (25, 50 and 100 ?mol/L) during early differentiation and maintenance stages. Cell viability and the state of lipid droplets were assessed by the MTT assay and Oil Red O, respectively, and the expression of beige-related genes and proteins was examined by RT-qPCR, Western blotting and flow cytometry. Nicotine did not alter adipocyte differentiation; however, it increased the expression of peroxisome proliferator- activated receptor gamma (PPAR?) protein during early differentiation and maintenance. Nicotine treatment during early differentiation downregulated gene and protein expression of PPAR? coactivator 1-alpha (PGC-1?), uncoupling protein 1 (UCP1) and cluster of differentiation 137 (CD137), and gene expression of Cbp/p300 interacting transactivator with Glu/ Asp rich carboxy-terminal domain 1 (Cited1), transmembrane protein 26 (Tmem26), and short stature homeobox 2 (Shox2). Nicotine treatment during the maintenance stage upregulated these beige-related genes/proteins. Nicotine treatment of immature adipocytes damaged beige function through a decrease in PGC-1?/UCP1 expression, but nicotine treatment of mature adipocytes or both immature and mature cells enhanced beige functioning. Nicotine induced beige-like phenotype dysfunction in 3T3-L1 adipocytes. This process may affect thermogenesis in adipose tissue and cause a dysfunction in fat metabolism.

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Fruit of Gardenia jasminoides Induces Mitochondrial Activation and Non-Shivering Thermogenesis through Regulation of PPARγ

Antioxidants ◽

10.3390/antiox10091418 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1418

Author(s):

Woo Yong Park ◽

Gahee Song ◽

Ja Yeon Park ◽

Kwan-Il Kim ◽

Kwang Seok Ahn ◽

...

Keyword(s):

Uncoupling Protein ◽

Exposure Model ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Gardenia Jasminoides ◽

White Adipocytes ◽

Beige Adipocytes ◽

Underlying Mechanisms ◽

Induced Changes

The extract of the Gardenia jasminoides fruit (GJFE) can been consumed as an herbal tea or used as a yellow dye. Recently, studies report that GFJE exerts inhibitory effects on lipid accumulation and adipogenesis in white adipocytes. We evaluated the thermogenic actions of GJFE by focusing on mitochondrial activation and studying the underlying mechanisms. To investigate the role of GJFE on thermogenesis in mice, we used an acute cold exposure model. After 2 weeks of feeding, the cold tolerance of GJFE-fed mice was notably increased compared to PBS-fed mice. This was due to an increase in thermogenic proteins in the inguinal white adipose tissue of the cold-exposed mice. Moreover, GJFE significantly increased thermogenic factors such as peroxisome proliferator-activated receptor gamma (PPARγ), uncoupling protein 1 (UCP1), and PPARγ coactivator 1 alpha (PGC1α) in vitro as well. Factors related to mitochondrial abundance and functions were also induced by GJFE in white and beige adipocytes. However, the treatment of PPARγ inhibitor abolished the GJFE-induced changes, indicating that activation of PPARγ is critical for the thermogenic effect of GJFE. In conclusion, GJFE induces thermogenic action by activating mitochondrial function via PPARγ activation. Through these findings, we suggest GJFE as a potential anti-obesity agent with a novel mechanism involving thermogenic action in white adipocytes.

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Effects of Deep Sea Water on Anti-Obesity Properties in Induction of Beige Adipocytes

Current Chemical Biology ◽

10.2174/2212796812666180705143429 ◽

2019 ◽

Vol 13 (1) ◽

pp. 38-48

Author(s):

Samihah Z.M. Nani ◽

Abubakar Jaafar ◽

Fadzilah A.A. Majid ◽

Akbariah Mahdzir ◽

Md. Nor Musa

Keyword(s):

Adipose Tissue ◽

Deep Sea ◽

Sea Water ◽

Binding Protein ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Fatty Acid Binding ◽

Deep Sea Water ◽

Beige Adipocytes

Objective: Deep sea water (DSW) accumulates many scientific shreds of evidence in treating obesity. Previous studies indicated that it reduces white adipose tissue (WAT) and body weight. WAT is energy storage fat, while beige adipose tissue is energy supply fat. In this study, the effects of DSW in the induction of beige adipocytes from mouse adipose tissue-derived stromal vascular fraction (SVF) cells are determined. Methods: Adipose tissue-derived SVF cells were isolated from mice and used for induction of beige adipocytes and treated with DSW at several concentrations. Results: During the course of beige adipocytes differentiation, DSW treatment increased lipid accumulation and upregulated adipogenic genes markers expression such as peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein a (C/EBP-α), and fatty acid binding protein 4 (FABP4), and also upregulated thermogenic genes markers such as the uncoupling protein 1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and cell deathinducing DFFA-like effector A (Cidea) in beige adipocytes. Conclusion: DSW has the potential to promote browning of WAT and upregulates the thermogenic genes that are responsible for energy expenditure.

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Screening of flavor compounds using Ucp1-luciferase reporter beige adipocytes identified 5-methylquinoxaline as a novel UCP1-inducing compoundsss

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab216 ◽

2021 ◽

Author(s):

Satoko Kawarasaki ◽

Kazuki Matsuo ◽

Hidetoshi Kuwata ◽

Lanxi Zhou ◽

Jungin Kwon ◽

...

Keyword(s):

High Throughput Screening ◽

Uncoupling Protein ◽

Mitochondrial Protein ◽

Whole Body ◽

Flavor Compounds ◽

Luciferase Reporter ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Beige Adipocytes ◽

Ucp1 Expression

Abstract Uncoupling protein 1 (UCP1) in brown or beige adipocytes is a mitochondrial protein that is expected to enhance whole-body energy expenditure. For the high-throughput screening of UCP1 transcriptional activity regulator, we established a murine inguinal white adipose tissue-derived Ucp1-luciferase reporter preadipocyte line. Using this reporter preadipocyte line, 654 flavor compounds were screened, and a novel Ucp1 expression-inducing compound, 5-methylquinoxaline, was identified. Adipocytes treated with 5-methylquinoxaline showed increased Ucp1 mRNA expression levels and enhanced oxygen consumption. 5-methylquinoxaline induced Ucp1 expression through peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and 5-methylquinoxaline-induced PGC1α activation seemed to be partially regulated by its phosphorylation or deacetylation. Thus, our Ucp1-luciferase reporter preadipocyte line is a useful tool for screening of Ucp1 inductive compounds.

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

Nutrients ◽

10.3390/nu13124214 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4214

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-ol (FL)s, 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, FLs possibly activate 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 FLs. In addition, we examined the impact of the repeated administration of 50 mg/kg FLs for 14 days on adipose tissues in mice. In BAT, FLs tended to increase the level of Ucp-1 along with significant increase of thermogenic transcriptome factors expressions, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR domain-containing (PRDM)1. Expression of browning markers, CD137 and transmembrane protein (TMEM) 26, in addition to PGC-1α were increased in epididymal adipose (eWAT) by FLs. A multilocular morphology with cell size reduction was shown in the inguinal adipose (iWAT), together with increasing the level of Ucp-1 by FLs. These results exert that FLs induce browning in adipose, and this change is possibly produced by the activation of the SNS.

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Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes

International Journal of Molecular Sciences ◽

10.3390/ijms20020274 ◽

2019 ◽

Vol 20 (2) ◽

pp. 274 ◽

Cited By ~ 7

Author(s):

Ana Yuliana ◽

Asumi Daijo ◽

Huei-Fen Jheng ◽

Jungin Kwon ◽

Wataru Nomura ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Uncoupling Protein 1 ◽

Peroxisome Proliferator Activated Receptor ◽

Beige Adipocytes ◽

Ucp1 Expression ◽

Er Homeostasis

Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 (Ucp1) involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of Ucp1 and peroxisome proliferator-activated receptor γ (Pparγ), which is known as a Ucp1 transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the Ucp1 enhancer, thereby downregulating Ucp1 expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on Ucp1 expression via Pparγ suppression in beige adipocytes.

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Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00380.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. C710-C719 ◽

Cited By ~ 131

Author(s):

Anna Vainshtein ◽

Liam D. Tryon ◽

Marion Pauly ◽

David A. Hood

Keyword(s):

Skeletal Muscle ◽

Acute Exercise ◽

Transmembrane Protein ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Lipid Trafficking ◽

Mitochondrial Transcription Factor ◽

Energy Demands ◽

Niemann Pick ◽

Exercise Induced

Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1α plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1α knockout (KO) animals. Deletion of PGC-1α resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1α. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1α that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1α. Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/ .

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A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210612 ◽

2021 ◽

pp. 1-17

Author(s):

Jessica Lynn ◽

Mingi Park ◽

Christiana Ogunwale ◽

George K. Acquaah-Mensah

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Mammalian Target Of Rapamycin ◽

Insulin Receptors ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Main Component ◽

The Impact

Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

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