Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Assimacopoulos-Jeannet, F.

doi:10.1038/sj.ijo.0802857

Cited by 55 publications

(19 citation statements)

References 45 publications

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“…The hypothesis that serine can mediate de novo sphingolipid synthesis in mammalian systems as well as yeast is further supported by data from a previous study demonstrating a burst of de novo sphingolipid synthesis upon medium change in J774A.1 cells that correlated directly to the serine concentration in medium (21). Interestingly an increased supply of exogenous free fatty acid to cultured cells can also stimulate de novo sphingolipid synthesis in skeletal muscle and cultured myo-tubes (47,48), pancreas (49), and several other tissues and/or tissue culture model systems (50 -52) often with pathophysiological consequences. Whether oversupply of serine can mediate similar effects is also under current investigation.…”

Section: Discussionsupporting

confidence: 65%

Selective Substrate Supply in the Regulation of Yeast de Novo Sphingolipid Synthesis

Cowart

Hannun

2007

Journal of Biological Chemistry

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The heat stress response of Saccharomyces cerevisiae is characterized by transient cell cycle arrest, altered gene expression, degradation of nutrient permeases, trehalose accumulation, and translation initiation of heat shock proteins. Importantly heat stress also induces de novo sphingolipid synthesis upon which many of these subprograms of the heat stress response depend. Despite extensive data addressing the roles for sphingolipids in heat stress, the mechanism(s) by which heat induces sphingolipid synthesis remains unknown. This study was undertaken to determine the events and/or factors required for heat stress-induced sphingolipid synthesis. Data presented indicate that heat does not directly alter the in vitro activity of serine palmitoyltransferase (SPT), the enzyme responsible for initiating de novo sphingolipid synthesis. Moreover deletion of the small peptide Tsc3p, which is thought to maximize SPT activity, specifically reduced production of C 20 sphingolipid species by over 70% but did not significantly decrease overall sphingoid base production. In contrast, the fatty-acid synthase inhibitor cerulenin nearly completely blocked sphingoid base production after heat, indicating a requirement for endogenous fatty acids for heat-mediated sphingoid base synthesis. Consistent with this, genetic studies show that fatty acid import does not contribute to heat-induced de novo synthesis under normal conditions. Interestingly the absence of medium serine also ameliorated heat-induced sphingoid base production, indicating a requirement for exogenous serine for the response, and consistent with this finding, disruption of synthesis of endogenous serine did not affect heat-induced sphingolipid synthesis. Serine uptake assays indicated that heat increased serine uptake from medium by 100% during the first 10 min of heat stress. Moreover treatments that increase serine uptake in the absence of heat including acute medium acidification and glucose treatment also enhanced de novo sphingoid base synthesis equivalent to that induced by heat stress. These data agree with findings from mammalian systems that availability of substrates is a key determinant of flux through sphingolipid synthesis. Moreover data presented here indicate that SPT activity can be driven by several factors that increase serine uptake in the absence of heat. These findings may provide insights into the many systems in which de novo synthesis is increased in the absence of elevated in vitro SPT activity.The contribution of sphingolipids to yeast biology has become increasingly appreciated because of recent findings that they regulate processes as diverse as endocytosis, cytoskeletal dynamics, ubiquitin-dependent proteolysis, the cell cycle, sporulation, translation, and post-translational protein assembly, modification, and routing (for reviews, see Refs. 1-3). In particular, the role of sphingolipids in stress responses has generated significant interest due to the discovery that heat stress induces transient flux through de novo sphingolipid sy...

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Section: Discussionsupporting

confidence: 65%

Selective Substrate Supply in the Regulation of Yeast de Novo Sphingolipid Synthesis

Cowart

Hannun

2007

Journal of Biological Chemistry

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“…When accumulation of lipids exceeds the energy expenditure, then most of the excess amount is stored in the form of FFAs in adipose and other insulin-sensitive tissues. When fat storage and energy supply is impaired in adipose tissues, elevation of FFAs levels in plasma occurs which is converted into the triglycerides and stores in non-adipose tissues [148]. The ectopic storage of FFAs metabolites (mostly triglycerides) results in lipotoxic effects in peripheral tissues (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked?

2016

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BackgroundInsulin resistance (IR) is one of the major hallmark for pathogenesis and etiology of type 2 diabetes mellitus (T2DM). IR is directly interlinked with various inflammatory responses which play crucial role in the development of IR. Inflammatory responses play a crucial role in the pathogenesis and development of IR which is one of the main causative factor for the etiology of T2DM.MethodsA comprehensive online English literature was searched using various electronic search databases. Different search terms for pathogenesis of IR, role of various inflammatory responses were used and an advanced search was conducted by combining all the search fields in abstracts, keywords, and titles.ResultsWe summarized the data from the searched articles and found that inflammatory responses activate the production of various pro-inflammatory mediators notably cytokines, chemokines and adipocytokines through the involvement of various transcriptional mediated molecular pathways, oxidative and metabolic stress. Overnutrition is one of the major causative factor that contributes to induce the state of low-grade inflammation due to which accumulation of elevated levels of glucose and/or lipids in blood stream occur that leads to the activation of various transcriptional mediated molecular and metabolic pathways. This results in the induction of various pro-inflammatory mediators that are decisively involved to provoke the pathogenesis of tissue-specific IR by interfering with insulin signaling pathways. Once IR is developed, it increases oxidative stress in β-cells of pancreatic islets and peripheral tissues which impairs insulin secretion, and insulin sensitivity in β-cells of pancreatic islets and peripheral tissues, respectively. Moreover, we also summarized the data regarding various treatment strategies of inflammatory responses-induced IR.ConclusionsIn this article, we have briefly described that how pro-inflammatory mediators, oxidative stress, transcriptional mediated molecular and metabolic pathways are involved in the pathogenesis of tissues-specific IR. Moreover, based on recent investigations, we have also described that to counterfeit these inflammatory responses is one of the best treatment strategy to prevent the pathogenesis of IR through ameliorating the incidences of inflammatory responses.

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“…In obesity, adipose tissue, skeletal muscle, and liver exhibit major abnormalities in sphingolipid metabolism that result in increased ceramide production, inflammation, and activation of pro-inflammatory cytokines, and impairments in glucose homeostasis and insulin responsiveness [8,14,25,39]. In both humans with NASH [40], and the C57BL/6 mouse model of diet-induced obesity with T2DM and NASH [41], ceramide levels in adipose tissue are elevated due to increased activation of sphingomyelin transferase, and acidic and neutral sphingomyelinases [29].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Ceramide-Mediated Neurodegeneration

Tong

2009

JAD

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Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be associated with cognitive impairment or early neurodegeneration. Previously, we showed that diet-induced obesity with T2DM and NASH results in mild neurodegeneration with some features of AD, including brain insulin resistance. In a companion study, we correlated obesity/T2DM/NASH-associated central nervous system (CNS) abnormalities with increased pro-ceramide gene expression in liver. Since ceramides are neurotoxic and cause insulin resistance, we directly investigated the role of ceramides as mediators of neurodegeneration using an in vitro culture model. We treated PNET2 human CNS neuronal cells with D-erythro-Ceramide analogs (C2Cer:N-acetylsphinganine and C6Cer: N-hexanoylsphinganine), or the inactive dihydroceramide analog (C2DCer) for 48 h, and probed for changes in genes and proteins that are critical to insulin/IGF signaling, and associated with neurodegeneration. Exposure to C6Cer > C2Cer impaired energy metabolism, viability, and insulin and insulin-like growth factor signaling mechanisms, and resulted in increased levels of AβPP-Aβ and pTau, whereas C2D had no significant effect on these parameters. CNS exposure to neurotoxic ceramides from exogenous sources, including liver, can cause neurodegeneration with impairments in insulin and IGF signaling mechanisms, similar to the findings in experimental models of obesity/T2DM, and NASH.

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Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Cited by 55 publications

References 45 publications

Selective Substrate Supply in the Regulation of Yeast de Novo Sphingolipid Synthesis

Selective Substrate Supply in the Regulation of Yeast de Novo Sphingolipid Synthesis

Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked?

Mechanisms of Ceramide-Mediated Neurodegeneration

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