Thiazole analog as stearoyl-CoA desaturase 1 inhibitor

Li, Chun Sing; Belair, Liette; Guay, Jocelyne; Murgasva, Renata; Sturkenboom, Wayne; Ramtohul, Yeeman K.; Zhang, Lei; Huang, Zheng

doi:10.1016/j.bmcl.2009.07.015

Cited by 39 publications

(16 citation statements)

References 13 publications

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“…Accordingly, efforts have been made to identify pharmacological inhibitors of SCD1. In agreement with results obtained in the SCD1 KO mouse [9], oral administration of a selective SCD1 inhibitor strongly repressed the diet-induced weight gain in C57BL6 mice as well as decreased the desaturation index (oleate/stearate) [15]. Also, the effects of reduced SCD1 were reproduced in rat models where SCD1 inhibition reduced plasma triglyceride levels and improved insulin sensitivity [16].…”

Section: Introductionsupporting

confidence: 81%

Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells

2010

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BackgroundStearoyl-CoA desaturase 1 (SCD1) is an ER resident enzyme introducing a double-bond in saturated fatty acids. Global knockout of SCD1 in mouse increases fatty acid oxidation and insulin sensitivity which makes the animal resistant to diet-induced obesity. Inhibition of SCD1 has therefore been proposed as a potential therapy of the metabolic syndrome. Much of the work has focused on insulin target tissue and very little is known about how reduced levels of SCD1 would affect the insulin-producing β-cell, however. The aim of the present study was therefore to investigate how reduced levels of SCD1 affect the β-cell.ResultsInsulin-secreting MIN6 cells with reduced levels of SCD1 were established by siRNA mediated knockdown. When fatty acid oxidation was measured, no difference between cells with reduced levels of SCD1 and mock-transfected cells were found. Also, reducing levels of SCD1 did not affect insulin secretion in response to glucose. To investigate how SCD1 knockdown affected cellular mechanisms, differentially regulated proteins were identified by a proteomic approach. Cells with reduced levels of SCD1 had higher levels of ER chaperones and components of the proteasome. The higher amounts did not protect the β-cell from palmitate-induced ER stress and apoptosis. Instead, rise in levels of p-eIF2α and CHOP after palmitate exposure was 2-fold higher in cells with reduced levels of SCD1 compared to mock-transfected cells. Accordingly, apoptosis rose to higher levels after exposure to palmitate in cells with reduced levels of SCD1 compared to mock-transfected cells.ConclusionsIn conclusion, reduced levels of SCD1 augment palmitate-induced ER stress and apoptosis in the β-cell, which is an important caveat when considering targeting this enzyme as a treatment of the metabolic syndrome.

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Section: Introductionsupporting

confidence: 81%

Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells

2010

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“…Whilst D9D/SCD1 is positively correlated with PPARγ to increase lipogenesis in adipocytes [20,37], the significance of reducing the D9D/SCD1 expression to reverse obesity has been constantly discussed [38,39]. Many anti-obesity compounds are designed with the aim of reducing the level of D9D/SCD1 [40,41], similar to the effect shown here by EPA. Bigger LDs has been shown to strongly correlate with the upregulation of PPARγ, D9D/SCD1 and Cidea in adipocytes supplemented with STA and OLA.…”

Section: Discussionmentioning

confidence: 99%

Suppressive actions of eicosapentaenoic acid on lipid droplet formation in 3T3-L1 adipocytes

2010

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BackgroundLipid droplet (LD) formation and size regulation reflects both lipid influx and efflux, and is central in the regulation of adipocyte metabolism, including adipokine secretion. The length and degree of dietary fatty acid (FA) unsaturation is implicated in LD formation and regulation in adipocytes. The aims of this study were to establish the impact of eicosapentaenoic acid (EPA; C20:5n-3) in comparison to SFA (STA; stearic acid, C18:0) and MUFA (OLA; oleic acid, C18:1n-9) on 3T3-L1 adipocyte LD formation, regulation of genes central to LD function and adipokine responsiveness. Cells were supplemented with 100 μM FA during 7-day differentiation.ResultsEPA markedly reduced LD size and total lipid accumulation, suppressing PPARγ, Cidea and D9D/SCD1 genes, distinct from other treatments. These changes were independent of alterations of lipolytic genes, as both EPA and STA similarly elevated LPL and HSL gene expressions. In response to acute lipopolysaccharide exposure, EPA-differentiated adipocytes had distinct improvement in inflammatory response shown by reduction in monocyte chemoattractant protein-1 and interleukin-6 and elevation in adiponectin and leptin gene expressions.ConclusionsThis study demonstrates that EPA differentially modulates adipogenesis and lipid accumulation to suppress LD formation and size. This may be due to suppressed gene expression of key proteins closely associated with LD function. Further analysis is required to determine if EPA exerts a similar influence on LD formation and regulation in-vivo.

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“…Also in humans, genetic variations in the Scd1 gene were found to be associated with body fat deposition and insulin sensitivity [30]. Some recent studies have used pharmacological inhibition of Scd1 for treatment of obesity and insulin resistance [31], [32]. Glucokinase (GcK) phosphorylates glucose to produce glucose-6-phosphate and therefore regulates glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

et al. 2010

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BackgroundLeptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss.Methodology/Principal FindingsWe utilized microarray technology to compare hepatic gene expression changes after two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented.Conclusions/SignificanceIn this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.

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Thiazole analog as stearoyl-CoA desaturase 1 inhibitor

Cited by 39 publications

References 13 publications

Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells

Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing β-cells

Suppressive actions of eicosapentaenoic acid on lipid droplet formation in 3T3-L1 adipocytes

Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

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