scholarly journals Implication of Ceramide Kinase in Adipogenesis

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Marta Ordoñez ◽  
Natalia Presa ◽  
Miguel Trueba ◽  
Antonio Gomez-Muñoz
Keyword(s):  
Critical Role ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Gene Encoding ◽  
Peroxisome Proliferator Activated Receptor ◽  
Growth And Survival ◽  
Ceramide Kinase ◽  
Proinflammatory Responses ◽  
Treatment Of Obesity ◽  
Low Grade Inflammation

Ceramide kinase (CerK) plays a critical role in the regulation of cell growth and survival and has been implicated in proinflammatory responses. In this work, we demonstrate that CerK regulates adipocyte differentiation, a process associated with obesity, which causes chronic low-grade inflammation. CerK was upregulated during differentiation of 3T3-L1 preadipocytes into mature adipocytes. Noteworthy, knockdown of CerK using specific siRNA to silence the gene encoding this kinase resulted in substantial decrease of lipid droplet formation and potent depletion in the content of triacylglycerols in the adipocytes. Additionally, CerK knockdown caused blockade of leptin secretion, an adipokine that is crucial for regulation of energy balance in the organism and that is increased in the obese state. Moreover, CerK gene silencing decreased the expression of peroxisome proliferator-activated receptor gamma (PPARγ), which is considered the master regulator of adipogenesis. It can be concluded that CerK is a novel regulator of adipogenesis, an action that may have potential implications in the development of obesity, and that targeting this kinase may be beneficial for treatment of obesity-associated diseases.

scholarly journals Lactobacillus rhamnosus GG Colonization in Early Life Ameliorates Inflammaging of Offspring by Activating SIRT1/AMPK/PGC-1α Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-27
Author(s):  
Tianyu Liu ◽  
Xueli Song ◽  
Yaping An ◽  
Xuemei Wu ◽  
Wanru Zhang ◽  
...  
Keyword(s):  
Early Life ◽  
Lactobacillus Rhamnosus ◽  
Intestinal Barrier ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Sequencing Analysis ◽  
Lactobacillus Rhamnosus Gg ◽  
Peroxisome Proliferator Activated Receptor ◽  
Age Related ◽  
Low Grade Inflammation

Inflammaging refers to chronic, low-grade inflammation during aging, which contributes to the pathogenesis of age-related diseases. Studies have shown that probiotic intervention in the aging stage could delay aging-related disorders. However, whether the application of probiotics in early life could have antiaging effects on offspring was unknown. Here, we investigated the effects of Lactobacillus rhamnosus GG (LGG) colonization in early life on inflammaging of offspring. Pregnant mice with the same conception time were given LGG live bacteria (LC group) or LGG fixed bacteria (NC group) from the 18th day after pregnancy until natural birth. The progeny mice were treated with 107 cfu of live or fixed LGG for 0-5 days after birth, respectively. LGG colonization could be detected in the feces of 3-week offspring. The 16S rRNA sequencing analysis of 3-week-old offspring showed that colonization of LGG in early life could alter the composition and diversity of gut microbiota. Interestingly, the beneficial effects of LGG colonization in early life on the microbiota lasted to 8 months old. The abundance of longevity-related bacteria (Lactobacillus, Bifidobacterium, and Akkermansia muciniphila) increased significantly in the LGG colonization group. In addition, LGG colonization increased the abundance of short-chain fatty acid- (SCFA-) producing bacteria and the production of cecal SCFAs. LGG colonization in early life protected the intestinal barrier, enhanced antioxidant defense, attenuated epithelial cell DNA damage, and inhibited intestinal low-grade inflammation in 8-month-old progeny mice. Mechanically, LGG could upregulate Sirtuin1 (SIRT1)/Adenosine 5 ′ -monophosphate-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) pathway and repress activation of nuclear factor-kappa B (NF-κB), while the protective effect of LGG was blunted after SIRT1 gene silencing. Together, LGG colonization in early life could ameliorate inflammaging of offspring, which would provide a new strategy for the prevention of age-related diseases.

scholarly journals PPARγ Activation Inhibits Growth and Survival of Human Endometriotic Cells by Suppressing Estrogen Biosynthesis and PGE2 Signaling.

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4803-4813 ◽  
Author(s):  
Dan I. Lebovic ◽  
Shahryar K. Kavoussi ◽  
JeHoon Lee ◽  
Sakhila K. Banu ◽  
Joe A. Arosh
Keyword(s):  
Cell Cycle ◽  
Stromal Cells ◽  
Cell Cycle Regulation ◽  
Chronic Inflammatory Disease ◽  
Reproductive Age ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Growth And Survival ◽  
Cycle Regulation ◽  
Estrogen Biosynthesis

Endometriosis is a chronic inflammatory disease of reproductive age women leading to chronic pelvic pain and infertility. Current antiestrogen therapies are temporizing measures, and endometriosis often recurs. Potential nonestrogenic or nonsteroidal targets are needed for treating endometriosis. Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear receptor, is activated by thiazolidinediones (TZDs). In experimental endometriosis, TZDs inhibit growth of endometriosis. Clinical data suggest potential use of TZDs for treating pain and fertility concurrently in endometriosis patients. Study objectives were to 1) determine the effects of PPARγ action on growth and survival of human endometriotic epithelial and stromal cells and 2) identify the underlying molecular links between PPARγ activation and cell cycle regulation, apoptosis, estrogen biosynthesis, and prostaglandin E2 biosynthesis and signaling in human endometriotic epithelial and stromal cells. Results indicate that activation of PPARγ by TZD ciglitazone 1) inhibits growth of endometriotic epithelial cells 12Z up to 35% and growth of endometriotic stromal cells 22B up to 70% through altered cell cycle regulation and intrinsic apoptosis, 2) decreases expression of PGE2 receptors (EP)2 and EP4 mRNAs in 12Z and 22B cells, and 3) inhibits expression and function of P450 aromatase mRNA and protein and estrone production in 12Z and 22B cells through EP2 and EP4 in a stromal-epithelial cell-specific manner. Collectively, these results indicate that PGE2 receptors EP2 and EP4 mediate actions of PPARγ by incorporating multiple cell signaling pathways. Activation of PPARγ combined with inhibition of EP2 and EP4 may emerge as novel nonsteroidal therapeutic targets for endometriosis-associated pain and infertility, if clinically proven safe and efficacious.

Abstract 15931: Glycogen Synthase Kinase-3α Plays a Critical Role in the Development of Cardiac Dysfunction During Obesity and Insulin Resistance Through Phosphorylation of Peroxisome Proliferator-Activated Receptor α

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Insulin Resistance ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Cardiac Dysfunction ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Obesity and insulin resistance (IR) lead to impaired cardiac metabolism, resulting in cardiac dysfunction. However, the underlying mechanisms responsible for the development of cardiac dysfunction remain poorly understood. PPARα serves as a key regulator of fatty acid (FA) metabolism in the heart. GSK-3α, a serine/threonine kinase, was dephosphorylated at S21 and activated (2.0 fold, p<0.05) in the hearts of obese mice fed a high-fat diet (HFD) and ob/ob mice. To evaluate the functional significance of GSK-3α upregulation, wild-type (WT) and cardiac specific GSK-3α heterozygous knockout (cGSK-3α HKO) mice were fed a HFD for up to 14 weeks. There was no difference in the food intake or body weight change between WT and cGSK-3α HKO mice. However, cardiac hypertrophy and diastolic dysfunction observed in WT mice were significantly ameliorated in cGSK-3α HKO mice after HFD feeding (8.1± 0.6 and 6.5±0.5, LVW/TL; 24.8±0.9 and 16.6±0.8, deceleration time (DT), all p<0.05). FA oxidation (FAO) (0.81 fold) and ectopic lipid accumulation (Oil Red O staining) were significantly decreased in cGSK-3α HKO mice than in WT mice after HFD feeding. GSK-3α, but not GSK-3β, directly interacted with and phosphorylated PPARα at the ligand binding domain in cardiomyocytes (CMs) and in the heart. PPARα phosphorylation in the heart was significantly increased (2.1 fold, p<0.05) in response to HFD, but it was attenuated in cGSK-3α HKO mice (0.74 fold, p<0.05). Fenofibrate, a PPARα ligand, inhibited GSK-3α-induced PPARα phosphorylation (0.81 fold, p<0.05), reduced ectopic lipid accumulation, FAO (0.84 fold, p<0.05), and attenuated diastolic dysfunction (25.5±3.1 and 18.6±2.5, DT; 0.16±0.04 and 0.08±0.02, EDPVR, all p<0.05) in the heart of HFD fed mice. Collectively, these results suggest that GSK-3α increases PPARα activity through phosphorylation of PPARα, which is inhibited by Fenofibrate. Activation of GSK-3α and consequent phosphorylation of PPARα during obesity and IR could play an important role in the development of cardiac hypertrophy and diastolic dysfunction. Synthetic PPARα ligands inhibit GSK-3α-mediated phosphorylation of PPARα, thereby paradoxically attenuating excessive FA metabolism in cardiomyocytes.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

scholarly journals Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism

2006 ◽  
Vol 92 (2) ◽  
pp. 386-395 ◽  
Author(s):  
Arya M. Sharma ◽  
Bart Staels
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Endocrine Function ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Abstract Context: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). Evidence Acquisition: Articles on the role of peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990–2006). Evidence Synthesis: Articles were assessed to provide a comprehensive overview of how PPARγ-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. Conclusions: PPARγ is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARγ activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFα, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARγ also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARγ activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARγ-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

scholarly journals Conditional Disruption of the Peroxisome Proliferator-Activated Receptor γ Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux

2002 ◽  
Vol 22 (8) ◽  
pp. 2607-2619 ◽  
Author(s):  
Taro E. Akiyama ◽  
Shuichi Sakai ◽  
Gilles Lambert ◽  
Christopher J. Nicol ◽  
Kimihiko Matsusue ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Gene Knockout ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exon 2 ◽  
Transgenic Mouse Line ◽  
Pparγ Gene

ABSTRACT Disruption of the peroxisome proliferator-activated receptor γ (PPARγ) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPARγ conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPARγ gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPARγ mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXRα, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPARγ-MXCre+ mice. Basal cholesterol efflux from cholesterol-loaded macrophages to HDL was significantly reduced after disruption of the PPARγ gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPARγ-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPARγ. Together, these data indicate that PPARγ plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.

scholarly journals Apple Flavonols Mitigate Adipocyte Inflammation and Promote Angiogenic Factors in LPS- and Cobalt Chloride-Stimulated Adipocytes, in Part by a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1386 ◽  
Author(s):  
Danyelle M. Liddle ◽  
Meaghan E. Kavanagh ◽  
Amanda J. Wright ◽  
Lindsay E. Robinson
Keyword(s):  
Mrna Expression ◽  
Cobalt Chloride ◽  
Nuclear Factor Κb ◽  
Diglycidyl Ether ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Anti Inflammatory

Adipose tissue (AT) expansion induces local hypoxia, a key contributor to the chronic low-grade inflammation that drives obesity-associated disease. Apple flavonols phloretin (PT) and phlorizin (PZ) are suggested anti-inflammatory molecules but their effectiveness in obese AT is inadequately understood. Using in vitro models designed to reproduce the obese AT microenvironment, 3T3-L1 adipocytes were cultured for 24 h with PT or PZ (100 μM) concurrent with the inflammatory stimulus lipopolysaccharide (LPS; 10 ng/mL) and/or the hypoxia mimetic cobalt chloride (CoCl2; 100 μM). Within each condition, PT was more potent than PZ and its effects were partially mediated by peroxisome proliferator-activated receptor (PPAR)-γ (p < 0.05), as tested using the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE). In LPS-, CoCl2-, or LPS + CoCl2-stimulated adipocytes, PT reduced mRNA expression and/or secreted protein levels of inflammatory and macrophage chemotactic adipokines, and increased that of anti-inflammatory and angiogenic adipokines, which was consistent with reduced mRNA expression of M1 polarization markers and increased M2 markers in RAW 264.7 macrophages cultured in media collected from LPS + CoCl2-simulated adipocytes (p < 0.05). Further, within LPS + CoCl2-stimulated adipocytes, PT reduced reactive oxygen species accumulation, nuclear factor-κB activation, and apoptotic protein expression (p < 0.05). Overall, apple flavonols attenuate critical aspects of the obese AT phenotype.

Anti-adipogenesis and antioxidative defense status of a crude extract of ‘Kalasin 2’ peanut sprouts in 3T3-L1 mouse adipocytes

2019 ◽  
Vol 97 (6) ◽  
pp. 740-749
Author(s):  
Tantip Boonsong ◽  
Siriporn Pakwan ◽  
Wanida Chawnawa
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Oxidative Status ◽  
Peroxisome Proliferator ◽  
Antioxidative Defense ◽  
Peroxisome Proliferator Activated Receptor ◽  
Defense Systems ◽  
Treatment Of Obesity ◽  
Mouse Adipocytes ◽  
And Oxidative Stress

The aim of this study was to investigate the effects of extracts from germinated (GPE) and non-germinated peanuts (NGPE) on adipogenesis and oxidative status in normal and oxidative-stress-induced 3T3-L1 mouse adipocytes. The treated cells were analysed for cell growth, lipid accumulation, levels of intracellular reactive oxygen species (ROS), and the expression levels of mRNAs and proteins related to adipogenesis and antioxidative defense systems. The results indicated that an extract from peanuts made 9 days after germination (9GPE) reduced lipid contents and mRNA expression of adipogenesis-related genes to a greater extent than an extract from peanuts made 1-day after germination (1GPE) or from NGPE, respectively. In oxidative-stress-induced adipocytes, 9GPE decreased ROS levels, lipid content, and the protein expression of peroxisome-proliferator-activated receptor gamma, and also increased the protein expression of antioxidants. These results illustrate the anti-adipogenic capacity and oxidative status improvement achievable with GPE, and that it could be used as a putative therapeutic agent in the prevention of and (or) treatment of obesity and diseases associated with oxidative stress.

scholarly journals Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1848 ◽  
Author(s):  
Miey Park ◽  
Anshul Sharma ◽  
Hae-Jeung Lee
Keyword(s):  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Adenosine Monophosphate ◽  
Immunoblot Analysis ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
White Adipocytes ◽  
Health Promoting ◽  
Treatment Of Obesity

Delphinidin-3-O-β-glucoside (D3G) is a health-promoting anthocyanin whose anti-obesity activity has not yet been thoroughly investigated. We examined the effects of D3G on adipogenesis and lipogenesis in 3T3-L1 adipocytes and primary white adipocytes using real-time RT-PCR and immunoblot analysis. D3G significantly inhibited the accumulation of lipids in a dose-dependent manner without displaying cytotoxicity. In the 3T3-L1 adipocytes, D3G downregulated the expression of key adipogenic and lipogenic markers, which are known as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1 (SREBP1), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty acid synthase (FAS). Moreover, the relative protein expression of silent mating type information regulation 2 homolog 1 (SIRT1) and carnitine palmitoyltransferase-1 (CPT-1) were increased, alongside reduced lipid levels and the presence of several small lipid droplets. Furthermore, D3G increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which suggests that D3G may play a role in AMPK and ACC activation in adipocytes. Our data indicate that D3G attenuates adipogenesis and promotes lipid metabolism by activating AMPK-mediated signaling, and, hence, could have a therapeutic role in the management and treatment of obesity.

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