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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. This cytokine induces insulin resistance, at least in part, through inhibition of the tyrosine kinase activity of the insulin receptor. Recently, a new class of compounds, the antidiabetic thiazolidinediones (TZDs), has been shown to improve insulin resistance in obesity and non-insulin-dependent diabetes mellitus in both rodents and man. Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPARgamma/ RXR complex is shown by the fact that similar effects are observed with other PPARgamma/RXR ligands such as 15 deoxy Delta12,14PGJ2 and LG268. The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions.
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PMID:Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. 931 88

Even among young, healthy individuals, there is more than a 10-fold variation in insulin sensitivity; however, taken in combination, all the known modifiers of insulin sensitivity - including obesity and a variety of environmental factors - explain less than one third of this variation. It is possible that genetic factors could account for the bulk of the variance observed, and hence play a major role in the development of impaired insulin sensitivity, ie insulin resistance. From the genetic point of view, insulin resistance is thought to be due to the inheritance of a number of mutations in a variety of genes. Three complementary approaches have been applied in the search for mutations: mutational analysis of candidate genes; linkage analysis of candidate genes or chromosomal regions for insulin resistance in familial type 2 diabetes; and random genome mapping with quantitative trait loci (QTL) analysis. Mutational analysis of the insulin signalling cascade has identified a glycine-arginine (Gly-Arg) substitution at codon 972 of the insulin receptor substrate-1 (IRS-1) gene with a carrier prevalence of 9% among Caucasians. Expression of this variant in 32-D cells is associated with a significant (20-30%) impairment of insulin-stimulated PI3-kinase activity, as well as reduced binding of IRS-1 to the p85 regulatory subunit of PI3-kinase. Genotype/phenotype studies stratified according to body mass index (BMI) indicate that obese subjects who are heterozygous for the mutant allele have a 50% decrease in insulin sensitivity, compared with wild-type obese subjects. This suggests that there may be an interaction between the mutant allele and obesity, such that, in the presence of obesity, the mutant variant may aggravate the obesity-associated insulin resistance. Mutational analysis has also shown that homozygous carriers of a codon Met 326 Ile mutation in the p85 subunit of phosphatidylinositol-3 (PI3)-kinase (about 2% of the Caucasian population) have lower glucose tolerance, glucose effectiveness. A further Asp to Tyr polymorphism has been identified at codon 905 of the gene encoding the regulatory subunit of glycogen-associated protein phosphatase-1 (PP1G). Individuals who are heterozygous for this polymorphism constitute 18% of the Caucasian population and appear to exhibit both tissue-specific and pathway-specific insulin resistance. It is likely that inherited insulin resistance will eventually prove to be related to subtle mutations in many such genes of the insulin signalling network and the numerous genetic components controlling energy metabolism.
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PMID:Genetics of insulin resistance. 1032 50

Insulin resistance is central to the pathophysiology of type 2 diabetes. It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. We studied the molecular basis of insulin resistance in mice in which injection with gold thioglucose led to the development of hyperphagia, obesity and insulin resistance over a 4-month period. We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. We investigated different mechanisms by which defects in the components of the insulin signalling cascade could emerge, including down-regulation and abnormal phosphorylation of signal molecules. In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. Increased IRS-1 phosphorylation on serine and threonine residues affects tyrosine phosphorylation. Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice.
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PMID:Molecular mechanisms of insulin action in normal and insulin-resistant states. 1032 50

Insulin exerts wide variety of biological effects through interaction with its specific receptor, which belongs to a large family of receptor tyrosine kinases. The activated insulin receptor phosphorylates the intracellular substrate IRS protains, which then bind various signalling molecules that contain Src homology 2 domains. The first downstram molecule that was shown to associate with IRS protains is PI3-kinase. PI3-kinase contributes to a wide variety of biological actions. Both Akt(PKB), a serine-threonine kinase with a PH domain, and atypical PKC(PKC zeta, PKC lambda) have been implicated as downstream effectors of PI3-kinase. Insulin resistance contributes to the pathogenesis of NIDDM. Both primary, genetically, and secondary, environmentally factors are important for insulin resistance. The secondary factors include hyperglycemia, hyperlipidemia, obesity, TNF alpha, FFA(free fatty acid).
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PMID:[Insulin signalling system and mechanism of insulin resistance]. 1070 48

The peroxisome proliferator activated receptors-gamma (PPARgamma) belong to the superfamily of nuclear transcription factors acting as master genes regulating events in adipocyte differentiation. Thus, PPARgamma is a candidate gene for affecting insulin sensitivity and the pathogenesis of insulin resistance. PPARs trigger endocrine response of two important adipose tissue-derived signalling factors, leptin and tumor necrosis factor-alpha. Leptin is the afferent signal in a negative feedback loop regulating adipose tissue mass and energy balance. It generates insulin-like signals for glucose transport and glycogen synthesis via leptin receptors and the PI3-kinase and could, therefore, play a role as a mediator of obesity-related insulin resistance. Recently, a silent substitution in the coding sequence of the PPARgamma2 gene, leading to the substitution of a C by a T in exon 6 (nt 161), was described. In a recent study, it was proposed that mutations in PPARgamma could play a role in individuals who are at increased risk for developing obesity and type 2 diabetes mellitus by influencing leptin levels. We therefore examined the prevalence of the CAC(His) --> CAT(His) mutation in non-diabetic first degree relatives of subjects with type 2 diabetes to determine a possible association of this mutation to leptin levels and insulin sensitivity. 138 probands were characterised by oral glucose tolerance tests, euglycemic-hyperinsulinemic glucose-clamp and by measuring leptin levels. We found 93 (67.4%) probands without the CAC(His) --> CAT(His) substitution and 45 heterozygotes (36.6%). When the whole group was analysed for an association of the mutation with plasma leptin concentration and insulin sensitivity, no statistical significance could be demonstrated. Independently of the mutation, leptin levels were significantly (p<0.001) higher in female subjects.
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PMID:The silent PPARgamma exon 6 CAC(His) --> CAT(His) polymorphism does not affect the plasma leptin levels in a collective of first degree relatives of type 2 diabetes patients from South West Germany. 1098 52

DHEA improves insulin sensitivity and has anti-obesity effect in animal models and men. However, the molecular mechanisms by which DHEA improves insulin action have not been clearly understood. In the present study, we examined the protein levels and phosphorylation state of insulin receptor (IR), IRS-1 and IRS-2, the association between IRSs and PI3K and SHP2, the insulin-induced IRSs associated PI 3-kinase activities, and the phosphorylation status of AKT and atypical PKCzeta/lambda in the liver and the muscle of 6 month-old Wistar rats treated with DHEA. There was no change in IR, IRS-1 and IRS-2 protein levels in both tissues of treated rats analysed by immunoblotting. On the other hand, insulin-induced IRS-1 tyrosine phosphorylation was increased in both tissues while IRS-2 tyrosyl phosphorylation was increased in liver of DHEA treated group. The PI3-kinase/AKT pathway was increased in the liver and the PI3K/atypical PKCzeta/lambda pathway was increased in the muscle of DHEA treated rats. These data indicate that these regulations of early steps of insulin action may play a role in the intracellular mechanism for the improved insulin sensitivity observed in this animal model.
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PMID:The phosphatidylinositol/AKT/atypical PKC pathway is involved in the improved insulin sensitivity by DHEA in muscle and liver of rats in vivo. 1550 80

Derivatives of 3-guanidinopropionic acid, such as leptin, reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, BVT.12777 activates intracellular signalling pathways in the arcuate nucleus in a manner analogous to leptin and insulin. In addition, because these hormones have been shown to activate K(ATP) channels in a subset of arcuate neurones, we examined whether this channel is also a functional endpoint for BVT.12777 in the arcuate nucleus. BVT.12777 transiently increased phosphorylation of MAPK, STAT3, PKB and GSK3, in a manner identical to that observed for leptin and insulin. BVT.12777 also hyperpolarized glucose-responsive neurones by increasing the activity of K(ATP) channels. The increase in K(ATP) activity driven by BVT.12777 was PI3-kinase independent, unlike leptin and insulin activation of this channel, and could also be elicited in isolated patches. However, K(ATP) activity induced by BVT.12777 was dependent on actin filament dynamics, both in intact neurones and isolated patches. Thus, BVT.12777 modulates arcuate neurone K(ATP) activity by re-organization of the cytoskeleton, a mechanism that has also been ascribed to leptin and insulin. Consequently, BVT.12777 appears to act as a leptin and insulin mimetic with respect to at least some elements of arcuate neurone intracellular signalling and the activation of K(ATP) channels. Resistance to leptin and insulin, associated with obesity has, at least in part, been postulated to be due to aberrant intracellular signalling in arcuate neurones. The data presented here indicate that it may be possible to develop drugs, which by-pass up-stream signalling components associated with adiposity hormone resistance, such as PI3-kinase, but can still induce functional outputs from arcuate neurones by targeting downstream components of the leptin and insulin signalling cascades.
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PMID:Activation of hypothalamic ATP-sensitive K+ channels by the aminoguanidine carboxylate BVT.12777. 1584 36

Increased expression of plasminogen activator inhibitor -1 (PAI-1) in adipose tissues is thought to contribute to both the cardiovascular and metabolic complications associated with obesity. Tumor necrosis factor alpha (TNF-alpha) is chronically elevated in adipose tissues of obese rodents and humans and has been directly implicated to induce PAI-1 in adipocytes. In this study, we used 3T3-L1 adipocytes to examine the mechanism by which TNF-alpha up-regulates PAI-1 in the adipocyte. Acute (3 h) and chronic (24 h) exposure of 3T3-L1 adipocytes to TNF-alpha induces PAI-1 mRNA by increasing the rate of transcription of the PAI-1 gene, and de novo protein synthesis is not required for this process. Although the p44/42 and PKC signaling pathways appear to be significant in the induction of PAI-1 mRNA in response to acute treatment with TNF-alpha, the more dramatic induction of PAI-1 mRNA observed in response to chronic exposure of adipocytes to TNF-alpha was mediated by these and additional signaling molecules, including p38, PI3-kinase, tyrosine kinases, and the transcription factor NF-kappaB. Moreover, the dramatic increase in PAI-1 observed after chronic exposure of adipocytes to TNF-alpha was accompanied by increased metabolic insulin resistance. Finally, we demonstrate that the PKC pathway is also central for PAI-1 induction in response to insulin and transforming growth factor-beta (TGF-beta), two additional molecules which are elevated in obesity and shown to directly induce PAI-1 in the adipocyte. The understanding of the mechanism of regulating PAI-1 expression in the adipocytes at the molecular level provides new insight to help identify novel targets in fighting the pathological complications of obesity.
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PMID:Molecular mechanisms of tumor necrosis factor-alpha-mediated plasminogen activator inhibitor-1 expression in adipocytes. 1592 93

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.
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PMID:Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. 1635 80

In obesity and diabetes, the ability of hypothalamic neurons to sense and transduce changes in leptin and insulin levels is compromised. The effects of both hormones require intracellular signalling via the PI3-kinase pathway, which is inhibited by the phosphatase PTEN. We show that leptin-stimulated F-actin depolymerization in mouse hypothalamic cells is inhibited by PTEN, a process involving independent effects of both its lipid and protein phosphatase activities. Potentially mediating this F-actin depolymerization, leptin, but not insulin, stimulated the phosphorylation of PTEN in a CK2 dependent manner, and inhibited its phosphatase activity. Similarly, hyperpolarization of mouse pancreatic beta-cells by leptin also requires coincident PtdIns(3,4,5)P3 generation and actin depolymerization, and could be inhibited by mechanisms requiring both the lipid and protein phosphatase activities of PTEN. These results demonstrate a critical role for PTEN in leptin signalling and indicate a mechanism by which leptin and insulin can produce PI3K dependent differential cellular outputs.
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PMID:A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic beta-cells. 1667 53


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