scholarly journals Protectin DX attenuates LPS-induced inflammation and insulin resistance in adipocytes via AMPK-mediated suppression of the NF-κB pathway

2018 ◽  
Vol 315 (4) ◽  
pp. E543-E551 ◽  
Author(s):  
Tae Woo Jung ◽  
Yoon Hee Chung ◽  
Hyoung-Chun Kim ◽  
A. M. Abd El-Aty ◽  
Ji Hoon Jeong
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Cell Types ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Monocyte Chemoattractant Protein 1 ◽  
Ampk Phosphorylation ◽  
Protectin Dx ◽  
Factor Α ◽  
Interfering Rna

Several studies have demonstrated that protectins, ω-3 fatty acid-derived proresolution mediators, may ameliorate inflammation. Recently, protectin DX (PDX) was also reported to attenuate inflammation and insulin resistance in several cell types. However, the effects of PDX on inflammation in adipocytes remain ambiguous. In this study, we found that PDX treatment suppressed adipogenesis and lipid accumulation during 3T3-L1 differentiation. Treatment of differentiated 3T3-L1 cells with PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation in a dose-dependent manner. PDX-induced AMPK phosphorylation blocked lipopolysaccharide (LPS)-induced secretion of proinflammatory cytokines, such as tumor necrosis factor-α and monocyte chemoattractant protein-1. Treatment of 3T3-L1 cells with PDX alleviated LPS-induced NF-κB and inhibitory factor κB phosphorylation. Furthermore, PDX treatment diminished LPS-induced impairment of insulin signaling and insulin-stimulated glucose uptake, as well as fatty acid oxidation. These effects were decreased by silencing AMPK expression with small-interfering RNA. In conclusion, the current findings suggest that PDX attenuates inflammation and insulin resistance in adipocytes via an AMPK-dependent pathway, which in turn provides evidence that PDX has anti-inflammatory and antidiabetic effects in adipocytes.

Thujone, a component of medicinal herbs, rescues palmitate-induced insulin resistance in skeletal muscle

2010 ◽  
Vol 299 (3) ◽  
pp. R804-R812 ◽  
Author(s):  
Hakam Alkhateeb ◽  
Arend Bonen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Glut4 Translocation ◽  
Palmitate Oxidation ◽  
Compound C ◽  
Ampk Phosphorylation

Thujone is thought to be the main constituent of medicinal herbs that have antidiabetic properties. Therefore, we examined whether thujone ameliorated palmitate-induced insulin resistance in skeletal muscle. Soleus muscles were incubated for ≤12 h without or with palmitate (2 mM). Thujone (0.01 mg/ml), in the presence of palmitate, was provided in the last 6 h of incubation. Palmitate oxidation, AMPK/acetyl-CoA carboxylase (ACC) phosphorylation and insulin-stimulated glucose transport, plasmalemmal GLUT4, and AS160 phosphorylation were examined at 0, 6, and 12 h. Palmitate treatment for 12 h reduced fatty acid oxidation (−47%), and insulin-stimulated glucose transport (−71%), GLUT4 translocation (−40%), and AS160 phosphorylation (−26%), but it increased AMPK (+51%) and ACC phosphorylations (+44%). Thujone (6–12 h) fully rescued palmitate oxidation and insulin-stimulated glucose transport, but only partially restored GLUT4 translocation and AS160 phosphorylation, raising the possibility that an increased GLUT4 intrinsic activity may also have contributed to the restoration of glucose transport. Thujone also further increased AMPK phosphorylation but had no further effect on ACC phosphorylation. Inhibition of AMPK phosphorylation with adenine 9-β-d-arabinofuranoside (Ara) (2.5 mM) or compound C (50 μM) inhibited the thujone-induced improvement in insulin-stimulated glucose transport, GLUT4 translocation, and AS160 phosphorylation. In contrast, the thujone-induced improvement in palmitate oxidation was only slightly inhibited (≤20%) by Ara or compound C. Thus, while thujone, a medicinal herb component, rescues palmitate-induced insulin resistance in muscle, the improvement in fatty acid oxidation cannot account for this thujone-mediated effect. Instead, the rescue of palmitate-induced insulin resistance appears to occur via an AMPK-dependent mechanism involving partial restoration of insulin-stimulated GLUT4 translocation.

Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts

2005 ◽  
Vol 288 (5) ◽  
pp. E900-E906 ◽  
Author(s):  
Rogayah Carroll ◽  
Andrew N. Carley ◽  
Jason R. B. Dyck ◽  
David L. Severson
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Transporter ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Palmitate Oxidation ◽  
Ampk Phosphorylation

Diabetic db/db mice exhibit profound insulin resistance in vivo, but the specific degree of cardiac insensitivity to insulin has not been assessed. Therefore, the effect of insulin on cardiomyocytes from db/db hearts was assessed by measuring two metabolic responses (deoxyglucose uptake and fatty acid oxidation) and the phosphorylation of two enzymes in the insulin-signaling cascade [Akt and AMP-activated protein kinase (AMPK)]. Maximal insulin-stimulated deoxyglucose transport was reduced to 58 and 40% of control in cardiomyocytes from db/db mice at two ages (6 and 12 wk). Insulin-stimulated deoxyglucose uptake was also reduced in myocytes from transgenic db/db mice overexpressing the insulin-sensitive glucose transporter ( db/db-hGLUT4). Treatment of db/db mice for 1 wk with an insulin-sensitizing peroxisome proliferator-activated receptor-γ agonist (COOH) completely normalized insulin-stimulated deoxyglucose uptake. Insulin had no direct effect on palmitate oxidation by either control or db/db cardiomyocytes, but the combination of insulin and glucose reduced palmitate oxidation, likely an indirect effect secondary to increased glucose uptake. Insulin had no effect on AMPK phosphorylation from either control or db/db cardiomyocytes. Insulin increased the phosphorylation of Akt in all cardiomyocyte preparations (control, db/db, COOH-treated db/db) to the same extent. Thus insulin has selective metabolic actions in mouse cardiomyocytes; deoxyglucose uptake and Akt phosphorylation are increased, but fatty acid oxidation and AMPK phosphorylation are unchanged. Insulin resistance in db/db cardiomyocytes is manifested by reduced insulin-stimulated deoxyglucose uptake.

scholarly journals TallyHO obese female mice experience poor reproductive outcomes and abnormal blastocyst metabolism that is reversed by metformin

2015 ◽  
Vol 27 (1) ◽  
pp. 31 ◽  
Author(s):  
Erica D. Louden ◽  
Kerri M. Luzzo ◽  
Patricia T. Jimenez ◽  
Tiffany Chi ◽  
Maggie Chi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Adverse Effects ◽  
Lipid Accumulation ◽  
Whole Body ◽  
Acid Oxidation ◽  
Obese Women ◽  
Reproductive Outcomes ◽  
Ampk Phosphorylation ◽  
Tnf Α

Obese women experience worse reproductive outcomes than normal weight women, specifically infertility, pregnancy loss, fetal malformations and developmental delay of offspring. The aim of the present study was to use a genetic mouse model of obesity to recapitulate the human reproductive phenotype and further examine potential mechanisms and therapies. New inbred, polygenic Type 2 diabetic TallyHO mice and age-matched control C57BL/6 mice were superovulated to obtain morula or blastocyst stage embryos that were cultured in human tubal fluid (HTF) medium. Deoxyglucose uptake was determined for individual insulin-stimulated blastocysts. Apoptosis was detected by confocal microscopy using the terminal deoxyribonucleotidyl transferase-mediated dUTP–digoxigenin nick end-labelling (TUNEL) assay and Topro-3 nuclear dye. Embryos were scored for TUNEL-positive as a percentage of total nuclei. AMP-activated protein kinase (AMPK) activation, tumour necrosis factor (TNF)-α expression and adiponectin expression were analysed by western immunoblot and confocal immunofluorescent microscopy. Lipid accumulation was assayed by BODIPY. Comparisons were made between TallyHO morulae cultured to blastocyst embryos in either HTF medium or HTF medium with 25 μg mL–1 metformin. TallyHO mice developed whole body abnormal insulin tolerance, had decreased litter sizes and increased non-esterified fatty acid levels. Blastocysts from TallyHO mice exhibited increased apoptosis, decreased insulin sensitivity and decreased AMPK. A possible cause for the insulin resistance and abnormal AMPK phosphorylation was the increased TNF-α expression and lipid accumulation, as detected by BODIPY, in TallyHO blastocysts and decreased adiponectin. Culturing TallyHO morulae with the AMPK activator metformin led to a reversal of all the abnormal findings, including increased AMPK phosphorylation, improved insulin-stimulated glucose uptake and normalisation of lipid accumulation. Women with obesity and insulin resistance experience poor pregnancy outcomes. Previously we have shown in mouse models of insulin resistance that AMPK activity is decreased and that activators of AMPK reverse poor embryo outcomes. Here, we show for the first time using a genetically altered obese model, not a diet-induced model, that metformin reverses many of the adverse effects of obesity at the level of the blastocyst. Expanding on this we determine that activation of AMPK via metformin reduces lipid droplet accumulation, presumably by eliminating the inhibitory effects of TNF-α, resulting in normalisation of fatty acid oxidation and HADH2 (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit) activity. Metformin exposure in vitro was able to partially reverse these effects, at the level of the blastocyst, and may thus be effective in preventing the adverse effects of obesity on pregnancy and reproductive outcomes.

Extending the glucose/fatty acid cycle: a glucose/adipose tissue cycle

2003 ◽  
Vol 31 (6) ◽  
pp. 1161-1164 ◽  
Author(s):  
M. Guerre-Millo
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Leptin Resistance ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Kinase Activation ◽  
Glucose Fatty Acid Cycle ◽  
Sensitizing Effect ◽  
Factor Α

It is now recognized that the WAT (white adipose tissue) produces a variety of bioactive peptides, collectively termed ‘adipokines’. Alteration of WAT mass in obesity or lipoatrophy affects the production of most adipose secreted factors. Since both conditions are associated with insulin resistance, the idea has emerged that certain adipokines might influence insulin action. Among these, tumour necrosis factor α, interleukin-6 and resistin are increased in the obese state and interfere negatively with insulin-mediated processes. Conversely, leptin and adiponectin exert an insulin-sensitizing effect, at least in part by favouring tissue fatty-acid oxidation through AMP-activated kinase activation. Obesity-induced insulin resistance has been linked to leptin resistance and decreased plasma adiponectin, while administration of leptin and adiponectin normalizes plasma levels in lipoatrophic mice and reverses insulin resistance. Thiazolidinedione anti-diabetic agents increase endogenous adiponectin production in rodents and humans, supporting the idea that drugs targeting adipokines might represent a new therapeutic approach to sensitize peripheral tissues to insulin.

scholarly journals Shikonin Attenuates Hepatic Steatosis by Enhancing Beta Oxidation and Energy Expenditure via AMPK Activation

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1133 ◽  
Author(s):  
So Young Gwon ◽  
Jiyun Ahn ◽  
Chang Hwa Jung ◽  
BoKyung Moon ◽  
Tae-Youl Ha
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Energy Expenditure ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Ampk Activation ◽  
High Fat ◽  
Ampk Phosphorylation

Shikonin, a natural plant pigment, is known to have anti-obesity activity and to improve insulin sensitivity. This study aimed to examine the effect of shikonin on hepatic steatosis, focusing on the AMP-activated protein kinase (AMPK) and energy expenditure in Hepa 1-6 cells and in high-fat fed mice. Shikonin increased AMPK phosphorylation in a dose- and time-dependent manner, and inhibition of AMPK with compound C inhibited this activation. In an oleic acid-induced steatosis model in hepatocytes, shikonin suppressed oleic acid-induced lipid accumulation, increased AMPK phosphorylation, suppressed the expression of lipogenic genes, and stimulated fatty acid oxidation-related genes. Shikonin administration for four weeks decreased body weight gain and the accumulation of lipid droplets in the liver of high-fat fed mice. Furthermore, shikonin promoted energy expenditure by activating fatty acid oxidation. In addition, shikonin increased the expression of PPARγ coactivator-1α (PGC-1α), carnitine palmitoyltransferase-1 (CPT1) and other mitochondrial function-related genes. These results suggest that shikonin attenuated a high fat diet-induced nonalcoholic fatty liver disease by stimulating fatty acid oxidation and energy expenditure via AMPK activation.

Skeletal muscle fatty acid oxidation is not directly associated with AMPK or ACC2 phosphorylation

2011 ◽  
Vol 36 (3) ◽  
pp. 361-367 ◽  
Author(s):  
Hakam Alkhateeb ◽  
Graham P. Holloway ◽  
Arend Bonen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Growing Body ◽  
C 50

Rescue of palmitate-induced insulin resistance has been linked with improvements in fatty acid oxidation, but importantly, not always with concurrently altered AMPK or ACC2 phosphorylation. Therefore, we examined the interrelationships among AMPK, ACC2, and fatty acid oxidation under 12 controlled conditions in isolated muscle. Incubation of soleus muscle (0–12 h) did not alter fatty acid oxidation, but did increase AMPK and ACC2 phosphorylation (24%–30%). Muscle incubation with palmitate (2 mmol·L–1) inhibited palmitate oxidation (∼55%), but paradoxically, this was associated with increased AMPK and ACC2 phosphorylation (∼50%). Addition of an AMPK activator (thujone) to control (no palmitate) muscle increased AMPK and ACC2 phosphorylation (∼25%) but did not alter palmitate oxidation. Addition of AMPK inhibitors, compound C (50 µmol·L–1) or adenine 9-β-d-arabinofuranoside (Ara; 2.5 mmol·L–1), to thujone-treated muscles (no palmitate) did not alter palmiate oxidation but reduced AMPK phosphorylation (32%–42%), while ACC2 phosphorylation remained above basal level (+14%–18%). Finally, in palmitate-treated muscle, thujone increased AMPK (+100%) and ACC2 phosphorylation (+52%) and restored palmitate oxidation. Compound C or Ara, administered along with thujone in palmitate-treated muscle, only partly blunted palmitate oxidation recovery despite inhibiting AMPK phosphorylation (–22%), although ACC2 phosphorylation remained upregulated (+33%). Among these experiments, AMPK phosphorylation and ACC2 phosphorylation were positively correlated. However, AMPK phosphorylation was not correlated with palmitate oxidation, and unexpectedly, palmitate oxidation was negatively correlated with ACC2 phosphorylation. Our study, in accordance with a growing body of evidence, indicates that neither AMPK phosphorylation nor ACC2 phosphorylation is by itself an appropriate marker of fatty acid oxidation, and further serves to question their regulatory role.

scholarly journals MicroRNA-27b-3p regulates function and metabolism in insulin resistance cells by inhibiting receptor tyrosine kinase-like orphan receptor 1

2018 ◽  
Vol 16 ◽  
pp. 205873921876205
Author(s):  
Yong Liu ◽  
Guohui Wang ◽  
Xiangwu Yang ◽  
Pengzhou Li ◽  
Hao Ling ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Tyrosine Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Receptor Tyrosine Kinase ◽  
Cell Model ◽  
Orphan Receptor ◽  
Acid Oxidation ◽  
Metabolism Disorder

Type 2 diabetes mellitus (T2DM) is associated with insulin resistance-induced lipid and glucose metabolism disorder. The study was aimed to explore the potential functional role of microRNA (miR)-27b-3p in T2DM, as well as underlying mechanisms. An insulin resistance cell model was induced in HepG2 cells and then expression of miR-27b-3p and receptor tyrosine kinase-like orphan receptor 1 (ROR1) was analyzed. The expression of miR-27b-3p was overexpressed or silenced, and the relationship between ROR1 and miR-27b-3p was investigated. Thereafter, the effects of miR-27b-3p on percentage of glucose uptake, fatty acid oxidation and cell cycle were analyzed. The expressions of miR-27b-3p were significantly increased, while the ROR1 levels were statistically decreased in the cells of the model group. Overexpression of miR-27b-3p dramatically decreased the levels of ROR1 and the percentage of glucose uptake, but had no effects on fatty acid oxidation. ROR1 was a target of miR-27b-3p. Moreover, overexpression of miR-27b-3p could remarkably highlight the percentages of cells at G0/G1 phase, but decreased the percentages of cells at S phase. In conclusion, our results suggest that miR-27b-3p regulates the function and metabolism of insulin resistance cells by inhibiting ROR1. miR-27b-3p might be a potential drug target in treating T2DM.

scholarly journals Pharmacologically targeting tribbles gene expression in colorectal cancer

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Victor Yassuda ◽  
Ana Luísa De Sousa-Coelho
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Types ◽  
Disease Recurrence ◽  
Rosemary Extract ◽  
Acid Oxidation ◽  
Data Sets ◽  
Compensatory Mechanism ◽  
Dependent Manner ◽  
Pharmacological Potential

Abstract Background TRIB1, TRIB2 and TRIB3 belong to the mammalian Tribbles family of pseudokinases proteins. Several studies reported Tribbles oncogenic role in different types of cancer, including colorectal cancer (CRC). Though current CRC treatment can be curative, patients are in risk of disease recurrence, meaning novel pharmacological targets and strategies are required. Our goal was to analyze Tribbles gene expression in CRC in response to different drugs. Methods Tribbles transcript levels were obtained from GEO profiles database (NCBI). Gene data sets (GDS) were selected based on experimental drug treatment description. Statistical analysis was performed at GraphPadPrism. Results Compared to non-treated control, TRIB2 expression was ∼2-fold increased in colorectal adenocarcinoma samples from patients treated with cyclooxygenase-2 inhibitor celecoxib (GDS3384), though not statistically significant (P < 0.1). TRIB1 was unaltered and data for TRIB3 was not available. By contrast, all Tribbles showed differential expression after treatment of SW620 colon cancer cells with supercritical rosemary extract in progressive increasing doses (0, 30, 60, 100 μg/mL) (P < 0.01;GDS5416). While both TRIB1 and TRIB3 were moderately increased in a dose-dependent manner (∼18% and 13%, respectively), TRIB2 was maximally down-regulated by ∼15% after 60 μg/mL. Conclusions Although celecoxib exhibits antiproliferative effects in different cancer cell types, TRIB2 gene expression showed a trend to be induced after treatment, in contrast to several genes involved in fatty acid oxidation that were down-regulated, which could result from a compensatory mechanism based on a metabolic shift. Since TRIB1/TRIB3 and TRIB2 were oppositely modulated in response to rosemary extract, additional studies are needed to validate its specific pharmacological potential interest for CRC treatment.

scholarly journals Hypothyroidism Intensifies Both Canonic and the De Novo Pathway of Peroxisomal Biogenesis in Rat Brown Adipocytes in a Time-Dependent Manner

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2248
Author(s):  
Marija Aleksic ◽  
Igor Golic ◽  
Andjelika Kalezic ◽  
Aleksandra Jankovic ◽  
Bato Korac ◽  
...  
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Time Dependent ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Tubular Structures ◽  
Thyroid Status ◽  
Brown Adipocytes ◽  
Peroxisomal Biogenesis ◽  
Mutual Regulation

Despite peroxisomes being important partners of mitochondria by carrying out fatty acid oxidation in brown adipocytes, no clear evidence concerning peroxisome origin and way(s) of biogenesis exists. Herein we used methimazole-induced hypothyroidism for 7, 15, and 21 days to study peroxisomal remodeling and origin in rat brown adipocytes. We found that peroxisomes originated via both canonic, and de novo pathways. Each pathway operates in euthyroid control and over the course of hypothyroidism, in a time-dependent manner. Hypothyroidism increased the peroxisomal number by 1.8-, 3.6- and 5.8-fold on days 7, 15, and 21. Peroxisomal presence, their distribution, and their degree of maturation were heterogeneous in brown adipocytes in a Harlequin-like manner, reflecting differences in their origin. The canonic pathway, through numerous dumbbell-like and “pearls on strings” structures, supported by high levels of Pex11β and Drp1, prevailed on day 7. The de novo pathway of peroxisomal biogenesis started on day 15 and became dominant by day 21. The transition of peroxisomal biogenesis from canonic to the de novo pathway was driven by increased levels of Pex19, PMP70, Pex5S, and Pex26 and characterized by numerous tubular structures. Furthermore, specific peroxisomal origin from mitochondria, regardless of thyroid status, indicates their mutual regulation in rat brown adipocytes.

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