scholarly journals Experimental Activation of Endocannabinoid System Reveals Antilipotoxic Effects on Cardiac Myocytes

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1932 ◽  
Author(s):  
Ewa Harasim-Symbor ◽  
Agnieszka Polak-Iwaniuk ◽  
Karolina Konstantynowicz-Nowicka ◽  
Patrycja Bielawiec ◽  
Barbara Malinowska ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Muscle ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
De Novo ◽  
Spontaneously Hypertensive Rat ◽  
Plasma Concentrations ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Metabolic Disturbances

Hypertension coincides with myocardial alternations in lipid (including sphingolipids) and glucose metabolism. The latest data indicate that accumulation of metabolically active lipids, especially ceramide (CER) and diacylglycerol (DAG) significantly influences intracellular signaling pathways along with inducing insulin resistance. Since, it was demonstrated that the endocannabinoid system (ECS) affects myocardial metabolism it seems to be a relevant tool in alleviating metabolic disturbances within the cardiac muscle due to hypertension. All designed experiments were conducted on the animal model of primary hypertension, i.e., spontaneously hypertensive rat (SHR) with chronic ECS activation by injections of fatty acid amide hydrolase (FAAH) inhibitor—URB597. Lipid analyses were performed using chromatography techniques (gas liquid, thin layer, and high performance liquid chromatography). Colorimetric and immunoenzymatic testes were applied in order to determine plasma concentrations of insulin and glucose. Total myocardial expression of selected proteins was measured by Western blotting and/or immunohistochemistry methods. SHRs exhibited significantly intensified myocardial de novo pathway of CER synthesis as well as DAG accumulation compared to the control Wistar Kyoto rats. Besides, intramyocardial level of potentially cardioprotective sphingolipid, i.e., sphingosine-1-phosphate was considerably decreased in SHRs, whereas URB597 treatment restored the level of this derivative. Unexpectedly, ECS upregulation protected overloaded cardiac muscle against CER and DAG accumulation. Moreover, chronic URB597 treatment improved intramyocardial insulin signaling pathways in both normotensive and hypertensive conditions. It seems that the enhanced ECS triggers protective mechanisms in the heart due to decreasing the level of lipid mediators of insulin resistance.

scholarly journals Deletion of Shp2 Tyrosine Phosphatase in Muscle Leads to Dilated Cardiomyopathy, Insulin Resistance, and Premature Death

2008 ◽  
Vol 29 (2) ◽  
pp. 378-388 ◽  
Author(s):  
Frederic Princen ◽  
Emilie Bard ◽  
Farah Sheikh ◽  
Sharon S. Zhang ◽  
Jing Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Dilated Cardiomyopathy ◽  
Glucose Uptake ◽  
Single Molecule ◽  
Intracellular Signaling ◽  
Striated Muscle ◽  
Tyrosine Phosphatase ◽  
Premature Mortality ◽  
Premature Death ◽  
Metabolic Disturbances

ABSTRACT The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-ζ/λ and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.

scholarly journals Insulin-Like Growth Factor (IGF)-I Stimulates Cell Proliferation and Induces IGF Binding Protein (IGFBP)-3 and IGFBP-5 Gene Expression in Cultured Growth Plate Chondrocytes via Distinct Signaling Pathways

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 3096-3104 ◽  
Author(s):  
Daniela Kiepe ◽  
Sonia Ciarmatori ◽  
Andreas Hoeflich ◽  
Eckhard Wolf ◽  
Burkhard Tönshoff
Keyword(s):  
Signaling Pathways ◽  
Growth Plate ◽  
Intracellular Signaling ◽  
De Novo ◽  
Growth Plate Chondrocytes ◽  
Intracellular Signaling Pathways ◽  
Igf I ◽  
Rat Growth ◽  
Igf Binding ◽  
Igfbp 3

Abstract The bioactivity of IGF-I in the cellular microenvironment is modulated by both inhibitory and stimulatory IGF binding proteins (IGFBPs), whose production is partially under control of IGF-I. However, little is known on the IGF-mediated regulation of these IGFBPs in the growth plate. We therefore studied the effect of IGF-I on IGFBP synthesis and the involved intracellular signaling pathways in two cell culture models of rat growth plate chondrocytes. In growth plate chondrocytes in primary culture, incubation with IGF-I increased the concentrations of IGFBP-3 and IGFBP-5 in conditioned cell culture medium in a dose- and time-dependent manner. Coincubation of IGF-I with specific inhibitors of the p42/44 MAPK pathway (PD098059 or U0126) completely abolished the stimulatory effect of IGF-I on IGFBP-3 mRNA expression but did not affect increased IGFBP-5 mRNA levels. In contrast, inhibition of the phosphatidylinositol-3 kinase signaling pathway by LY294002 abrogated both IGF-I-stimulated IGFBP-3 and -5 mRNA expression. Comparable results regarding IGFBP-5 were obtained in the mesenchymal chondrogenic cell line RCJ3.1C5.18, which does not express IGFBP-3. The IGF-I-induced IGFBP-5 gene expression required de novo mRNA transcription and de novo protein synthesis. These data suggest that IGF-I modulates its activity in cultured rat growth plate chondrocytes by the synthesis of both inhibitory (IGFBP-3) and stimulatory (IGFBP-5) binding proteins. The finding that IGF-I uses different and only partially overlapping intracellular signaling pathways for the regulation of two IGFBPs with opposing biological functions might be important for the modulation of IGF bioactivity in the cellular microenvironment.

scholarly journals Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

2019 ◽  
Vol 20 (3) ◽  
pp. 479 ◽  
Author(s):  
Cécile L. Bandet ◽  
Sophie Tan-Chen ◽  
Olivier Bourron ◽  
Hervé Le Stunff ◽  
Eric Hajduch
Keyword(s):  
Insulin Resistance ◽  
De Novo ◽  
Critical Role ◽  
Plasma Concentrations ◽  
Muscle Cells ◽  
High Plasma ◽  
Sphingolipid Metabolism ◽  
Peripheral Tissues ◽  
Muscle Insulin Resistance ◽  
Increased Risk

Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.

scholarly journals Acylcarnitines activate proinflammatory signaling pathways

2014 ◽  
Vol 306 (12) ◽  
pp. E1378-E1387 ◽  
Author(s):  
Jennifer M. Rutkowsky ◽  
Trina A. Knotts ◽  
Kikumi D. Ono-Moore ◽  
Colin S. McCoin ◽  
Shurong Huang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Plasma Concentrations ◽  
Raw 264.7 Cells ◽  
Luciferase Reporter ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Luciferase Reporter Gene ◽  
Hct 116 ◽  
A Chain

Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed d,l isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant l-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. l-C14 carnitine (5–25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, l-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, l-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.

New mutations and pathogenesis of myeloproliferative neoplasms

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1723-1735 ◽  
Author(s):  
William Vainchenker ◽  
François Delhommeau ◽  
Stefan N. Constantinescu ◽  
Olivier A. Bernard
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
De Novo ◽  
Clonal Selection ◽  
Myeloproliferative Neoplasms ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Janus Kinase ◽  
Prognostic Impact ◽  
Loss Of Function

Abstract Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature blood cells. In the majority of classic MPN—polycythemia vera, essential thrombocythemia, and primitive myelofibrosis—driver oncogenic mutations affecting Janus kinase 2 (JAK2) or MPL lead to constitutive activation of cytokine-regulated intracellular signaling pathways. LNK, c-CBL, or SOCSs (all negative regulators of signaling pathways), although infrequently targeted, may either drive the disease or synergize with JAK2 and MPL mutations. IZF1 deletions or TP53 mutations are mainly found at transformation phases and are present at greater frequency than in de novo acute myeloid leukemias. Loss-of-function mutations in 3 genes involved in epigenetic regulation, TET2, ASXL1, and EZH2, may be early events preceding JAK2V617F but may also occur late during disease progression. They are more frequently observed in PMF than PV and ET and are also present in other types of malignant myeloid diseases. A likely hypothesis is that they facilitate clonal selection, allowing the dominance of the JAK2V617F subclone during the chronic phase and, together with cooperating mutations, promote blast crisis. Their precise roles in hematopoiesis and in the pathogenesis of MPN, as well as their prognostic impact and potential as a therapeutic target, are currently under investigation.

scholarly journals Mediterranean diet consumption affects the endocannabinoid system in overweight and obese subjects: possible links with gut microbiome, insulin resistance and inflammation

2021 ◽  
Author(s):  
Silvia Tagliamonte ◽  
Manolo Laiola ◽  
Rosalia Ferracane ◽  
Marilena Vitale ◽  
Maria A. Gallo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Mediterranean Diet ◽  
Gut Microbiome ◽  
Plasma Concentrations ◽  
Endocannabinoid System ◽  
Model Assessment ◽  
Weight Changes ◽  
Body Weight Changes ◽  
Obese Subjects

Abstract Purpose To investigate whether a Mediterranean diet (MD) affected the plasma concentrations of endocannabinoids (ECs), N-acylethanolamines (NAEs) and their specific ratios in subjects with lifestyle risk factors for metabolic diseases. To identify the relationship between circulating levels of these compounds and gut microbiome, insulin resistance and systemic inflammation. Methods A parallel 8-week randomised controlled trial was performed involving 82 overweight and obese subjects aged (mean ± SEM) 43 ± 1.4 years with a BMI of 31.1 ± 0.5 kg/m2, habitual Western diet (CT) and sedentary lifestyle. Subjects were randomised to consume an MD tailored to their habitual energy and macronutrient intake (n = 43) or to maintain their habitual diet (n = 39). Endocannabinoids and endocannabinoid-like molecules, metabolic and inflammatory markers and gut microbiome were monitored over the study period. Results The MD intervention lowered plasma arachidonoylethanolamide (AEA, p = 0.02), increased plasma oleoylethanolamide/palmitoylethanolamide (OEA/PEA, p = 0.009) and OEA/AEA (p = 0.006) and increased faecal Akkermansia muciniphila (p = 0.026) independent of body weight changes. OEA/PEA positively correlated with abundance of key microbial players in diet–gut–health interplay and MD adherence. Following an MD, individuals with low-plasma OEA/PEA at baseline decreased homeostatic model assessment of insulin resistance index (p = 0.01), while individuals with high-plasma OEA/PEA decreased serum high-sensitive C-reactive protein (p = 0.02). Conclusions We demonstrated that a switch from a CT to an isocaloric MD affects the endocannabinoid system and increases A. muciniphila abundance in the gut independently of body weight changes. Endocannabinoid tone and microbiome functionality at baseline drives an individualised response to an MD in ameliorating insulin sensitivity and inflammation. Clinical Trial Registry number and website NCT03071718; www.clinicaltrials.gov

Sign in / Sign up

Export Citation Format

Share Document