Human Obesity and Type 2 Diabetes Are Associated With Alterations in SREBP1 Isoform Expression That Are Reproduced Ex Vivo by Tumor Necrosis Factor-α

Sewter, Ciaran; Berger, Dirk; Considine, Robert V.; Medina, Gema; Rochford, Justin J.; Ciaraldi, Theodore P.; Henry, Robert R.; Dohm, Lynis; Flier, Jeffrey S.; O’Rahilly, Stephen; Vidal-Puig, António

doi:10.2337/diabetes.51.4.1035

Cited by 130 publications

(119 citation statements)

References 36 publications

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“…Work in our lab has shown that in human WAT, the majority of SREBP1 expressed is in the SREBP1c isoform. 35 In addition, SREBP1c expression is higher in human mature adipocytes than in both undifferentiated and differentiated primary adipocytes. This suggests that mature adipocytes are the component of the WAT in which SREBP1c is likely to have its greatest effects.…”

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 98%

“…The decrease in SREBP1 mRNA can be reproduced in human primary adipocyte cultures using TNFa. 35 Treatment for 24 h specifically decreases SREBP1c mRNA and can block the effect of insulin on mature SREBP1 protein. Interestingly, more recent work has shown that the inhibitory effect of TNFa on insulin-stimulated increases of mature SREBP1 protein can be reproduced in rat primary adipocyte culture model and is reproduced by C2-ceramide (Lelliott and Vidal-Puig, unpublished data).…”

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 99%

“…Many groups have established that insulin upregulates SREBP1c mRNA and mature SREBP1 protein and is accompanied by increases in FA biosynthetic gene expression. [33][34][35] As the product of the ACC-catalysed reaction, there is also an increase in the levels of malonyl-CoA, leading to the inhibition of CPT1 and mitochondrial FA oxidation (Figure 3). Work in our lab has shown that in human WAT, the majority of SREBP1 expressed is in the SREBP1c isoform.…”

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 99%

“…We have also been able to show that SREBP1 mRNA and protein expression in WAT and at mRNA level in skeletal muscle is increased by insulin. 35 This suggested that SREBP1 is regulated in both of these insulin sensitive tissues. It is not surprising in this respect that in lean vs morbidly obese humans, SREBP1 gene expression is decreased in adipose tissue of the morbidly obese group.…”

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 99%

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Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

2004

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Obesity and type 2 diabetes mellitus are the major noncommunicable public health problem of the 21st century. The best strategy to tackle this problem is to develop strategies to prevent/treat obesity. However, it is becoming clear that despite successful research identifying weight regulatory pathways, the development of the obesity epidemic is outpacing scientific progress. The lack of success controlling the obesity epidemic in an aging population will result in another subsequent uncontrolled epidemic of complications. Our research focuses on the mechanisms causing lipotoxicity aiming to identify suitable strategies to prevent or at least retard the development of the metabolic syndrome. Previous work using transgenic and knockout mouse models has shown an interplay between white adipose tissue and skeletal muscle linking fatty acid (FA) synthesis with reciprocal effects on FA oxidation. Work from our lab and others suggests that defective adipose tissue is a key link between obesity, insulin resistance and type 2 diabetes mellitus by promoting the development of lipotoxicity in peripheral tissues. We propose a series of models to describe the process by which the adipose tissue could react to an energy-rich environment and responds depending on genetic and physiological factors, impacting on the functions of other peripheral tissues. We suggest that by examining hypotheses that encompass multiple organs and the partitioning of energy between these organs, a suitable strategy can be devised for the treatment of chronic obesity.

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Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 98%

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 99%

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 99%

Section: Srebp1c a Gatekeeper For Lipotoxicitymentioning

confidence: 99%

See 2 more Smart Citations

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

2004

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“…There is now evidence both in humans and in rodents that SREBP-1c mediates insulin upregulation of genes encoding glycolytic and lipogenic enzymes in skeletal muscle, [42][43][44][45][46] but most fascinating are the very recent demonstrations that glucose alone (in the absence of insulin) can stimulate de novo lipogenesis in skeletal muscle cells. The evidence can be summarized as follows:…”

Section: Stimulatory Effects Of Glucose On Muscle De Novo Lipogenesismentioning

confidence: 99%

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

et al. 2004

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Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), (ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently (iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

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A rare missense mutation in a type 2 diabetes patient decreases the transcriptional activity of human sterol regulatory element binding protein-1

et al. 2006

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Sterol regulatory element binding protein 1 (SREBP-1) transcription factors play a key role in energy homeostasis by regulating genes involved in both carbohydrate and lipid metabolism, and in adipocyte differentiation. The 5' end of the mRNA-encoding SREBP-1 exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5' exons, each of which is spliced to a common exon 2. Mutations in the sterol regulatory element binding protein gene (SREBF)-1 may contribute to insulin resistance states. However, the variants described to date do not affect the SREBP function. In this study, we investigated the functional consequences of a novel missense mutation common to both SREBP-1 isoforms identified in a Spanish type 2 diabetic patient (c.677C>T, SREBP-1a p.T226M; c.605C>T, SREBP-1c p.T202M). Using reporter gene analysis and electrophoretic mobility shift assays, we found that this variant impairs the transcriptional activity and reduces DNA binding ability despite its comparable protein stability to the wild-type SREBP-1. This decreased activity impairs the expression of known downstream targets, such as the LDL receptor and fatty acid synthase genes. Our findings suggest that the threonine residue and/or surrounding region play an important role in the SREBP-1 function.

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Human Obesity and Type 2 Diabetes Are Associated With Alterations in SREBP1 Isoform Expression That Are Reproduced Ex Vivo by Tumor Necrosis Factor-α

Cited by 130 publications

References 36 publications

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

A rare missense mutation in a type 2 diabetes patient decreases the transcriptional activity of human sterol regulatory element binding protein-1

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