PI3K and AKT at the Interface of Signaling and Metabolism

Solinas, Giovanni; Becattini, Barbara

doi:10.1007/978-3-031-06566-8_13

Cited by 8 publications

(11 citation statements)

References 155 publications

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“…The PI3K-Akt signaling pathway is a key node for controlling the cell growth, multiplication and metabolism in mammalian cells [Pompura & Dominguez-Villar, 2018]. The action of PI3K-Akt signaling pathway could induce cells to proliferate abnormally, and the inhibited PI3K-Akt signaling pathway resulted in growth defects [Solinas & Becattini, 2022]. Various studies have shown that PI3K-Akt signaling pathway could promote the proliferation and anti-apoptosis of immature germ cells [Deng, et al, 2021].…”

Section: Discussionmentioning

confidence: 99%

DIA-based proteomics analysis of the protective effect of EGCG on cyclophosphamide-induced testicular injury in mice

Chunyan¹

2023

Preprint

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Cyclophosphamide (CP) impacts several types of normal and healthy tissues, especially reproductive organ. The current work sought to investigate the preventive role of the green tea ingredient epigallocatechin-3-gallate (EGCG) against CP-induced testicular damage in mice. Thirty mature male mice were randomly allocated to three groups (n=10). Group 1 functioned as the control. Group 2 was administered Mod with CP (50mg/kg/d) for five days. Group 3 received CP (50mg/kg/d) for 5 days and EGCG (80mg/kg/d) for the following 30 days. The findings demonstrated that EGCG enhanced testicular mass and indix. Evaluation of Histology and Transmission Electron microscopy analysis revealed that EGCG treatment mitigated CP-induced injury to testicular structures such spermatogonial cells and seminiferous tubules. A proteomics investigation of testis revealed that EGCG administration substantially affected the quantity of 863 proteins. GO and KEGG analysis revealed that these proteins were mostly found throughout development cell grouth and PI3K-Akt signaling pathway. The PPI network analysis and RT-PCR results showed that Cdk1, Kif11, and Aurka may be the targets for EGCG. This is the first study to indicate the preventive role of EGCG on CP-induced testicular damage, and EGCG might be a natural active ingredient for tolerance to the testis toxicity generated by CP.

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Section: Discussionmentioning

confidence: 99%

DIA-based proteomics analysis of the protective effect of EGCG on cyclophosphamide-induced testicular injury in mice

Chunyan¹

2023

Preprint

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“…In humans and rodents, induction of lipolysis with b-adrenergic agonists stimulates insulin secretion (Imura et al, 1971;Porte, 1967;Sennitt et al, 1985), and inhibition of lipolysis with nicotinic acid (NA) reduces insulin secretion in fasting (Balasse and Ooms, 1973;Boden et al, 1998;Dobbins et al, 1998a;Dobbins et al, 1998b;Stein et al, 1996). Considering the opposing actions of b-adrenergic signaling and InsR-PI3K signaling on adipocyte lipolysis (Guilherme et al, 2022;Solinas and Becattini, 2022), we hypothesized that insulin secretion is governed by adipocyte InsR-PI3K signaling.…”

Section: Introductionmentioning

confidence: 98%

“…This capacity of different species to precisely match insulin secretion with insulin sensitivity over a wide range of serum insulin indicates a conserved crosstalk between the metabolic action of insulin and insulin secretion. The metabolic action of insulin depends on the induction of phosphoinositide-3 kinase (PI3K) - AKT signaling in insulin target cells (Solinas and Becattini, 2022). Pharmacological inhibition of either the insulin receptor (InsR), PI3K, or AKT causes hyperglycemia and hyperinsulinemia in humans and rodents (Ando et al, 2014; Hopkins et al, 2018; Kalinsky et al, 2018; Patnaik et al, 2016; von Mehren et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, we have found that in humans with different adiposity and insulin sensitivity, fasting plasma insulin was not associated with blood glucose but was associated with adipose tissue lipolysis (Fryk et al, 2021). Considering the opposing actions of β-adrenergic signaling and InsR-PI3K signaling on adipocyte lipolysis (Guilherme et al, 2022; Solinas and Becattini, 2022), we hypothesized that insulin secretion is governed by adipocyte InsR-PI3K signaling.…”

Section: Introductionmentioning

confidence: 99%

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Adipocyte PI3K Links Adipostasis with Basal Insulin Secretion Through an Adipoincretin Effect

Becattini

Molinaro

Henricsson

et al. 2023

Preprint

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Inhibitors of insulin-PI3K signaling potently induce insulin secretion in-vivo, demonstrating that insulin secretion is governed by feedback control. Resolving the mechanism of this feedback is necessary to understand hyperinsulinemia and insulin resistance and to develop optimal PI3K-targeted therapies. Adipose tissue-specific knockout mice for the insulin receptor, or AKT1 and AKT2, are severely lipodystrophic. Thereby, the role of adipocyte insulin signaling in the feedback control of insulin secretion remains unknown. To investigate insulin-PI3K signaling in the adipocyte in vivo, we generated adipocyte-specific PI3Kalpha knockout mice (PI3K alphaAdQ). PI3Kalpha AdQ mice and PI3Kalpha F/F control mice showed similar adiposity, indicating compensation from another PI3K activity. PI3Kbeta-selective inhibitors dumped AKT phosphorylation, specifically in the adipocytes of PI3K alpha AdQ mice. The PI3Kbeta-selective inhibitor GSK2636771 markedly increased serum FFA and insulin secretion in PI3Kalpha AdQ mice but not in PI3KalphaF/F mice, demonstrating that insulin secretion is governed by adipocyte PI3K, a phenomenon that we name the adipoincretin effect. The adipoincretin effect can be induced in mice fasted overnight with decreasing glycemia. The effects of adipocyte-specific PI3K inhibition on insulin secretion and serum FFA could be partly dissociated by cotreating PI3Kalpha AdQ mice with GSK2636771 and the lipolysis inhibitor nicotinic acid. The adipoincretin effect was associated with reduced plasma branched-chain amino acids, reduced serum leptin, and increased 3-hydroxybutyrylcarnitine. These results demonstrate that baseline insulin secretion and lipolysis are coregulated by adipocyte PI3K signaling to control adipostasis during fasting through an adipoincretin effect.

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“…In humans and rodents, induction of lipolysis with b-adrenergic agonists stimulates insulin secretion [19][20][21] , and inhibition of lipolysis with nicotinic acid (NA) reduces insulin secretion in fasting [22][23][24][25][26] . Considering the opposing actions of badrenergic signaling and InsR-PI3K signaling on adipocyte lipolysis 27,28 , we hypothesized that insulin secretion is governed by adipocyte InsR-PI3K signaling.…”

Section: Introductionmentioning

confidence: 99%

Adipocyte PI3K links adipostasis with basal insulin secretion through an adipoincretin effect

Becattini

Molinaro

Henricsson

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Inhibitors of insulin-PI3K signaling potently induce insulin secretion in-vivo, demonstrating that insulin secretion is governed by feedback control. Resolving the mechanism of this feedback is necessary to understand hyperinsulinemia and insulin resistance and to develop optimal PI3K-targeted therapies. Adipose tissue-specific knockout mice for the insulin receptor, or AKT1 and AKT2, are severely lipodystrophic. Thereby, the role of adipocyte insulin signaling in the feedback control of insulin secretion remains unknown. To investigate insulin-PI3K signaling in the adipocyte in vivo, we generated adipocyte-specific PI3Ka knockout mice (PI3KaAdQ). PI3KaAdQ mice and PI3KaF/F control mice showed similar adiposity, indicating compensation from another PI3K activity. PI3Kb-selective inhibitors dumped AKT phosphorylation, specifically in the adipocytes of PI3KaAdQ mice. The PI3Kb-selective inhibitor GSK2636771 markedly increased serum FFA and insulin secretion in PI3KaAdQ mice but not in PI3KaF/F mice, demonstrating that insulin secretion is governed by adipocyte PI3K, a phenomenon that we name the adipoincretin effect. The adipoincretin effect can be induced in mice fasted overnight with decreasing glycemia. The effects of adipocyte-specific PI3K inhibition on insulin secretion and serum FFA could be partly dissociated by cotreating PI3KaAdQ mice with GSK2636771 and the lipolysis inhibitor nicotinic acid. The adipoincretin effect was associated with reduced plasma branched-chain amino acids, reduced serum leptin, and increased 3-hydroxybutyrylcarnitine. These results demonstrate that baseline insulin secretion and lipolysis are coregulated by adipocyte PI3K signaling to control adipostasis during fasting through an adipoincretin effect.

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PI3K and AKT at the Interface of Signaling and Metabolism

Cited by 8 publications

References 155 publications

DIA-based proteomics analysis of the protective effect of EGCG on cyclophosphamide-induced testicular injury in mice

DIA-based proteomics analysis of the protective effect of EGCG on cyclophosphamide-induced testicular injury in mice

Adipocyte PI3K Links Adipostasis with Basal Insulin Secretion Through an Adipoincretin Effect

Adipocyte PI3K links adipostasis with basal insulin secretion through an adipoincretin effect

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