Treatment of genetically obese mice with the iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin reduces body weight by decreasing food intake and increasing fat oxidation

Langeveld, Mirjam; Berg, Sjoerd A.A. van den; Bijl, Nora; Bijland, Silvia; Roomen, Cindy P. van; Houben-Weerts, Judith H.P.M.; Ottenhoff, Roelof; Dijk, Ko Willems van; Romijn, Johannes A.; Groen, Albert K.; Aerts, Johannes M. F. G.; Voshol, Peter J.

doi:10.1016/j.metabol.2011.05.013

Cited by 4 publications

(7 citation statements)

References 37 publications

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“…Numbers of myeloid (mDC) and plasmacytoid (pDC) DCs were decreased. pDC from GD showed a decrease in IFN-␣ production after TLR-9 stimulation compared with controls, in which ERT restored their function (27,28,96). Both myeloid and plasmacytoid DC and the yield of the monocyte-derived DC were obtained due to a decrease in GM-CSF and IL-4 stimulation.…”

Section: Patients With Gaucher's Disease Before and After Enzyme Replmentioning

confidence: 88%

“…Induction of fatty acid ␤-oxidation and plasma lipids was observed, indicating that AMP-DNM revised the preexisting NASH (100,104,170). Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation, a decrease in carbohydrate oxidation, and a reduction in food intake (96,100,171). The effect was associated with increased plasma level of the appetite-regulating peptide YY (96,100,171).…”

Section: Glucosylceramide Synthase Inhibitors and Other Inhibitors Ofmentioning

confidence: 96%

“…These molecules have effect in signal transduction and in the pathogenesis of several diseases (1,2,76,80,92,96). Cer is the simplest molecule in this family, and it serves as a precursor for the synthesis of the three main types of complex SLs (SMs, GSLs, and gangliosides), respectively.…”

Section: Sphingolipid Steady State In Health and Diseasementioning

confidence: 99%

“…Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation, a decrease in carbohydrate oxidation, and a reduction in food intake (96,100,171). The effect was associated with increased plasma level of the appetite-regulating peptide YY (96,100,171). The L-ido derivative of 2,L-ido-AMP-DNM, a selective inhibitor of GSL synthesis, lowered visceral GSLs in ob/ob mice and ZDF rats, with no inhibition of sucrase activity or sucrose assimilation being less effective in reducing blood glucose and HbA1c (172,178,182).…”

Section: Glucosylceramide Synthase Inhibitors and Other Inhibitors Ofmentioning

confidence: 99%

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Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Ilan

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.

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Section: Patients With Gaucher's Disease Before and After Enzyme Replmentioning

confidence: 88%

Section: Glucosylceramide Synthase Inhibitors and Other Inhibitors Ofmentioning

confidence: 96%

Section: Sphingolipid Steady State In Health and Diseasementioning

confidence: 99%

Section: Glucosylceramide Synthase Inhibitors and Other Inhibitors Ofmentioning

confidence: 99%

See 2 more Smart Citations

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Ilan

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The rates of fatty acid beta-oxidation and glucose oxidation were determined using metabolic cages, revealing that shortly after exposure to AMP-DNM, fat oxidation was nearly doubled (0.07 to 0.16 kcal.h −1 in the nocturnal period and 0.10 to 0.19 kcal.h −1 in the diurnal period). On the opposite, carbohydrate oxidation was markedly reduced by AMP-DNM treatment (0.43 to 0.28 kcal.h −1 in the nocturnal period and 0.34 to 0.20 kcal.h −1 in the diurnal period [25]. Other researchers have also reported beneficial effect of iminosugars on hepatic fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 91%

Correction of Liver Steatosis by a Hydrophobic Iminosugar Modulating Glycosphingolipids Metabolism

et al. 2012

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The iminosugar N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of glycosphingolipid (GSL) biosynthesis is known to ameliorate diabetes, insulin sensitivity and to prevent liver steatosis in ob/ob mice. Thus far the effect of GSL synthesis inhibition on pre-existing NASH has not yet been assessed. To investigate it, LDLR(−/−) mice were kept on a western-type diet for 12 weeks to induce NASH. Next, the diet was continued for 6 weeks in presence or not of AMP-DNM in the diet. AMP-DNM treated mice showed less liver steatosis, inflammation and fibrosis. Induction of fatty acid beta-oxydation was observed, as well as a reduction of plasma lipids. Our study demonstrates that AMP-DNM treatment is able to significantly correct pre-existing NASH, suggesting that inhibiting GSL synthesis may represent a novel strategy for the treatment of this pathology.

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The consequences of genetic and pharmacologic reduction in sphingolipid synthesis

Schiffmann

2014

J of Inher Metab Disea

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A new therapy based on substrate synthesis reduction in sphingolipidoses is showing promise. The consequences of decreasing sphingolipid synthesis depend on the level at which synthetic blockage occurs and on the extent of the blockage. Complete synthetic blockage may be lethal if it includes all sphingolipids, such as in a global knockout of serine palmitoyltransferase. Partial inhibition of sphingolipid synthetic pathways is usually benign and may have beneficial effects in a number of lysosomal diseases and in more common pathologies, as seen in animal models for atherosclerosis, polycystic kidney disease, diabetes, and asthma. Studies of various forms of sphingolipid synthesis reduction serve to highlight not only the cellular role of these lipids but also the potential risks and therapeutic benefits of pharmacological agents to be used in therapy for human diseases.

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Treatment of genetically obese mice with the iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin reduces body weight by decreasing food intake and increasing fat oxidation

Cited by 4 publications

References 37 publications

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

Correction of Liver Steatosis by a Hydrophobic Iminosugar Modulating Glycosphingolipids Metabolism

The consequences of genetic and pharmacologic reduction in sphingolipid synthesis

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