Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation

Hancer, Nancy J.; Qiu, Wei Qiao; Cherella, Christine E; Li, Yedan; Copps, Kyle D.; White, Morris F.

doi:10.1074/jbc.m114.554162

Cited by 85 publications

(84 citation statements)

References 91 publications

(110 reference statements)

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“…These observations provide further strong support for a causal negative impact of mitochondrial ROS production on AKTdependent insulin signaling, which agrees with previous observations (1)(2)(3)(4)(5). UnAG effects were associated with enhanced inhibitory IRS-1 S312 phosphorylation; this seemingly paradoxical observation is, however, consistent with reports of IRS-1 S312 phosphorylation as a physiological negative feedback modulation following downstream signaling activation (31).…”

Section: Discussionsupporting

confidence: 69%

“…These effects were further associated with enhanced IRS-1 S312 phosphorylation (Fig. 3B), an mTORC-dependent negative feedback mechanism and marker for enhanced insulin signaling (31). To determine whether activating IRS-1 phosphorylations were also enhanced, we measured pIRS-1 Y612 and found no stimulation in UnAG-treated animals (Supplementary Fig.…”

Section: Unag Enhances Insulin Signaling and Glucose Uptakementioning

confidence: 99%

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Unacylated Ghrelin Reduces Skeletal Muscle Reactive Oxygen Species Generation and Inflammation and Prevents High-Fat Diet–Induced Hyperglycemia and Whole-Body Insulin Resistance in Rodents

et al. 2016

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Excess reactive oxygen species (ROS) generation and inflammation may contribute to obesity-associated skeletal muscle insulin resistance. Ghrelin is a gastric hormone whose unacylated form (UnAG) is associated with whole-body insulin sensitivity in humans and may reduce oxidative stress in nonmuscle cells in vitro. We hypothesized that UnAG 1) lowers muscle ROS production and inflammation and enhances tissue insulin action in lean rats and 2) prevents muscle metabolic alterations and normalizes insulin resistance and hyperglycemia in high-fat diet (HFD)-induced obesity. In 12-week-old lean rats, UnAG (4-day, twice-daily subcutaneous 200-mg injections) reduced gastrocnemius mitochondrial ROS generation and inflammatory cytokines while enhancing AKT-dependent signaling and insulinstimulated glucose uptake. In HFD-treated mice, chronic UnAG overexpression prevented obesity-associated hyperglycemia and whole-body insulin resistance (insulin tolerance test) as well as muscle oxidative stress, inflammation, and altered insulin signaling. In myotubes, UnAG consistently lowered mitochondrial ROS production and enhanced insulin signaling, whereas UnAG effects were prevented by small interfering RNA-mediated silencing of the autophagy mediator ATG5. Thus, UnAG lowers mitochondrial ROS production and inflammation while enhancing insulin action in rodent skeletal muscle. In HFDinduced obesity, these effects prevent hyperglycemia and insulin resistance. Stimulated muscle autophagy could contribute to UnAG activities. These findings support UnAG as a therapeutic strategy for obesity-associated metabolic alterations.Clustered metabolic abnormalities, including excess reactive oxygen species (ROS) generation and inflammation activation, are proposed contributors to the onset of skeletal muscle insulin resistance (1-5). Excess muscle ROS production and inflammation are indeed linked at the level of inhibitor of kB (IkB)/nuclear factor-kB (NF-kB) activation and may cause insulin resistance by inhibiting insulin signaling downstream of insulin receptor (2,3,5). Ghrelin is a peptide hormone predominantly secreted by the stomach, and its acylated form (AG) is a major hypothalamic orexigenic signal (6,7). Sustained AG administration causes weight gain and hyperglycemia despite enhanced muscle mitochondrial oxidative capacity (8,9) by increasing food intake, hepatic gluconeogenesis, and fat deposition in rodents (10,11). A comprehensive understanding of the metabolic impact of ghrelin, however, has recently been allowed by reports of independent, more favorable effects of its unacylated form (UnAG). Although no specific UnAG receptor has yet been identified, UnAG counteracts glucogenic effects of AG as well as

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Section: Discussionsupporting

confidence: 69%

Section: Unag Enhances Insulin Signaling and Glucose Uptakementioning

confidence: 99%

Unacylated Ghrelin Reduces Skeletal Muscle Reactive Oxygen Species Generation and Inflammation and Prevents High-Fat Diet–Induced Hyperglycemia and Whole-Body Insulin Resistance in Rodents

et al. 2016

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“…In this report, we have presented a transcriptional mechanism whereby carrageenan exposure leads to increased mRNA expression of GRB10 by GATA2 activation of the GRB10 promoter, with attention to Ser 307 of IRS1. Multiple sites of serine/threonine phosphorylation of IRS1 have been identified (39) and might also participate in the cascade of reactions described in this report but have not yet been evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…These reactions lead to increased nuclear GATA2 and transcriptional activation of GRB10, which feeds back to inhibit Tyr(P)-IRS1. These interactions provide mechanistic links between the increase in Ser(P) 307 -IRS1 and the decline in Tyr(P)-IRS1 and help to clarify the relationship between Ser(P) 307 -IRS1 and Tyr(P)-IRS1 (39). Phosphorylations of IRS1 and their impact on the regulation of insulin sensitivity and propagation of insulin signaling have been considered in detail (39 -42).…”

Section: Discussionmentioning

confidence: 99%

Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1

Bhattacharyya

Feferman

Tobacman

2015

Journal of Biological Chemistry

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Background:The common food additive carrageenan inhibits insulin signaling by increasing Ser(P) 307 -IRS1, leading to reduced Ser(P) 473 -AKT. Results: Carrageenan also inhibits insulin signaling by increasing expression of GRB10, an inhibitor of Tyr(P)-IRS1. Conclusion: Combined effects of carrageenan on Tyr(P)-IRS1 and Ser(P) 307 -IRS1 completely block the insulin-induced increase in Ser(P) 473 -AKT. Significance: Carrageenan impairs glucose tolerance by inflammatory and transcriptional effects that lead to insulin resistance.

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“…Indeed, S6K1 participates in insulinmediated cell growth but-like mTORC1-also operates negative feedback loops at various levels of regulation. For example, several studies have shown that both mTORC1 and/or S6K1 phosphorylate specific serine residues on IRS proteins [6,7]. Moreover, some of these IRS-1 sites, notably Ser 1101 and Ser 636, were differentially regulated by mTOR and S6K1 [8,9].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Aims/hypothesis The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. Methods We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Results Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Conclusions/interpretation Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

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Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation

Cited by 85 publications

References 91 publications

Unacylated Ghrelin Reduces Skeletal Muscle Reactive Oxygen Species Generation and Inflammation and Prevents High-Fat Diet–Induced Hyperglycemia and Whole-Body Insulin Resistance in Rodents

Unacylated Ghrelin Reduces Skeletal Muscle Reactive Oxygen Species Generation and Inflammation and Prevents High-Fat Diet–Induced Hyperglycemia and Whole-Body Insulin Resistance in Rodents

Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

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