scholarly journals Phospholipase C-related catalytically inactive protein acts as a positive regulator for insulin signalling in adipocytes

2021 ◽  
Author(s):  
Jing Gao ◽  
Akiko Mizokami ◽  
Hiroshi Takeuchi ◽  
Aonan Li ◽  
Fei Huang ◽  
...  
Keyword(s):  
Cell Surface ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Phospholipase C ◽  
Insulin Signalling ◽  
Insulin Receptor Substrate ◽  
Wild Type ◽  
Immunoprecipitation Assay ◽  
Central Molecule ◽  
Inactive Protein

Insulin signalling is tightly controlled by various factors, but the exact molecular mechanism remains incompletely understood. We previously reported that phospholipase C-related but catalytically inactive protein (PRIP) interacts with Akt, the central molecule in insulin signalling. Here, we investigated whether PRIP is involved in the regulation of insulin signalling in adipocytes. We found that insulin signalling including insulin-stimulated phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Akt, and glucose uptake, were impaired in adipocytes from PRIP-knockout (KO) mice compared with those from wild-type (WT) mice. The amount of IR expressed on the cell-surface was decreased in PRIP-KO adipocytes. Immunoprecipitation assay showed that PRIP interacted with IR. The reduced cell-surface IR in PRIP-KO adipocytes was comparable with that in WT cells when Rab5 expression was silenced using specific siRNA. In contrast, the dephosphorylation of IRS-1 at serine residues, some of which were reported to be involved in the internalisation of IR, was impaired in cells from PRIP-KO mice. These results suggest that PRIP facilitates insulin signalling by modulating the internalisation of IR in adipocytes.

scholarly journals Losartan counteracts the effects of cardiomyocyte swelling on glucose uptake and insulin receptor substrate-1 levels

Peptides ◽  
2017 ◽  
Vol 96 ◽  
pp. 38-43
Author(s):  
Yamil Gerena ◽  
Janice Griselle Lozada ◽  
Bryan Jael Collazo ◽  
Jarold Méndez-Álvarez ◽  
Jennifer Méndez-Estrada ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes

2000 ◽  
Vol 275 (33) ◽  
pp. 25494-25501 ◽  
Author(s):  
Mathias Fasshauer ◽  
Johannes Klein ◽  
Kohjiro Ueki ◽  
Kristina M. Kriauciunas ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Essential Role ◽  
Insulin Receptor Substrate ◽  
Glut4 Translocation ◽  
Insulin Stimulation ◽  
Brown Adipocytes ◽  
Stimulation Of

scholarly journals Essential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes

2001 ◽  
Vol 21 (1) ◽  
pp. 319-329 ◽  
Author(s):  
Mathias Fasshauer ◽  
Johannes Klein ◽  
Kristina M. Kriauciunas ◽  
Kohjiro Ueki ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Cell Lines ◽  
Fatty Acid Synthase ◽  
Glucose Transporter ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Insulin Receptor Substrate ◽  
Differentiation Process ◽  
Wild Type

ABSTRACT The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARγ, or C/EBPα but not the thiazolidinedione troglitazone. Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. Akt phosphorylation was reduced in parallel with the total PI 3-kinase activity. Inhibition of PI 3-kinase with LY294002 blocked differentiation of wild-type cells. Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARγ and C/EBPα.

scholarly journals A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration

2005 ◽  
Vol 392 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Antonio J. Ruiz-Alcaraz ◽  
Hui-Kang Liu ◽  
Daniel J. Cuthbertson ◽  
Edward J. Mcmanus ◽  
Simeen Akhtar ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling ◽  
Insulin Injection ◽  
Underlying Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Insulin Receptor Tyrosine Kinase ◽  
Cell Culture Systems ◽  
Or Gene

Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.

scholarly journals Aldosterone Inhibits Insulin-Induced Glucose Uptake by Degradation of Insulin Receptor Substrate (IRS) 1 and IRS2 via a Reactive Oxygen Species-Mediated Pathway in 3T3-L1 Adipocytes

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1662-1669 ◽  
Author(s):  
Tsutomu Wada ◽  
Satoshi Ohshima ◽  
Eriko Fujisawa ◽  
Daisuke Koya ◽  
Hiroshi Tsuneki ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Glucocorticoid Receptor ◽  
Insulin Receptor ◽  
Receptor Antagonist ◽  
Glucose Uptake ◽  
Reactive Oxygen ◽  
Insulin Receptor Substrate ◽  
Oxygen Species ◽  
Metabolic Signaling

Serum aldosterone level is clinically known to correlate with body weight and insulin resistance. Because the underlying molecular mechanism is largely unknown, we examined the effect of aldosterone on insulin-induced metabolic signaling leading to glucose uptake in 3T3-L1 adipocytes. Aldosterone reduced the amounts of insulin receptor substrate (IRS) 1 and IRS2 in a time- and dose-dependent manner. As a result, insulin-induced phosphorylation of Akt-1 and -2, and subsequent uptake of 2-deoxyglucose were decreased. Degradation of IRSs was effectively prevented by a glucocorticoid receptor antagonist and antioxidant N-acetylcysteine, but not by a mineralocorticoid receptor antagonist. Because aldosterone induced phosphorylation of IRS1 at Ser307, responsible kinases were investigated, and we revealed that rapamycin and BMS345541, but neither SP600125 nor calphostin C, conferred for degradation of IRSs. Although lactacystin prevented the degradation of IRSs, glucose uptake was not preserved. Importantly, sucrose-gradient-sediment intracellular fraction analysis revealed that lactacystin did not effectively restore the reduction of IRS1 in the low-density microsome fraction, important for the transduction of insulin’s metabolic signaling. These results indicate that aldosterone deteriorates metabolic action of insulin by facilitating the degradation of IRS1 and IRS2 via glucocorticoid receptor-mediated production of reactive oxygen species, and activation of IκB Kinase β and target of rapamycin complex 1. Thus, aldosterone appears to be a novel key factor in the development of insulin resistance in visceral obesity.

scholarly journals Interleukin-1β-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 241-251 ◽  
Author(s):  
Jennifer Jager ◽  
Thierry Grémeaux ◽  
Mireille Cormont ◽  
Yannick Le Marchand-Brustel ◽  
Jean-François Tanti
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Protein Kinase B ◽  
Transcriptional Level ◽  
Insulin Receptor Substrate ◽  
Down Regulation ◽  
Glut 4

Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1β level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1β to alter insulin signaling and action remains to be explored. We demonstrated that IL-1β slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1β treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1β slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1β-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1β reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1β is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.

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