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Review
. 2022 Dec 5;23(23):15330.
doi: 10.3390/ijms232315330.

The PI3K/Akt Pathway in Meta-Inflammation

Maricedes Acosta-Martinez  1 , Maria Zulema Cabail  2
Affiliations
Review

The PI3K/Akt Pathway in Meta-Inflammation

Maricedes Acosta-Martinez et al. Int J Mol Sci. .

Abstract

Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity's negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network not only transduces metabolic information but also regulates macrophages' intracellular changes, which are responsible for their phenotypic switch towards a more proinflammatory state. In the present review, we discuss how the crosstalk between macrophages and adipocytes contributes to meta-inflammation and provide an overview on the involvement of the PI3K/Akt signaling pathway, and how its impairment contributes to the development of insulin resistance.

Keywords: Akt; PI3K; adipocytes; macrophages; meta-inflammation; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Insulin Signaling in Insulin-responsive Cell. In healthy individuals, insulin binds to the ectodomain of IRs, causing a conformational change that leads to the autophosphorylation of the tyrosine residues in the cytoplasmic β subunits. The IRS then binds to the phosphorylated tyrosine residues of IRs, causing them to be phosphorylated. Phosphorylated IRSs bind to PI3K, and as a consequence, PI3K is activated and converts PIP2 to PIP3. PIP3 recruits the serine/threonine kinase Akt (also known as protein kinase B) to the plasma membrane, where it is activated by phosphorylation. The activated Akt is responsible for the translocation of GLUT4 to the plasma membrane, allowing the entry of glucose into the cell, which will be used to produce ATP through mitochondrial oxidative phosphorylation. Activated Akt also promotes the inhibition of GSK3B, which leads to higher glycogen synthesis. Once activated, Akt also inhibits transcription factor FOXO1, which promotes transcription of lipoprotein lipase, an enzyme responsible for the breakdown of triglycerides. Furthermore, phosphorylated Akt inhibits TSC1/2, and as a consequence, mTORC1 is activated, which leads to protein synthesis. Activation of S6K1 by mTORC1 phosphorylates inhibitory serine residues on the IRS, while mTORC1-induced activation of GRB10 prevents insulin signaling by binding to IR. (Created with BioRender.com on 19 October 2022). Abbreviations: IRs, insulin receptors; IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase; PDK1, 3-phosphoinositide-dependent protein kinase 1; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; GLUT4, glucose transporter type 4; GSK3B, glycogen synthase kinase 3β; FOXO1, forkhead box O; TSC1/2, tuberous sclerosis protein complex 1 and 2; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; S6K1, S6 kinase 1; GRB10, growth-factor-receptor-bound protein 10.
Figure 2
Figure 2
PI3K/Akt Signaling in Adipose Tissue Macrophages. Bacterial LPSs or SFAs stimulate TLR4, which recruits the adapter protein MyD88. Following activation of the TLR4/MyD88 axis, IRAK1 and IRAK4 are recruited and interact with TRAF6 proteins, which subsequently phosphorylate the IKK complex (IKKβ, IKKα and NEMO). The activation of IKK further phosphorylates IκB proteins, leading to its ubiquitination and proteasomal degradation and freeing NF-κB complexes (p50–p65). NF-κB then translocates to the nucleus, where it regulates the expression of proinflammatory genes. Activation of IKK inhibits TSC1/2, the negative regulator of mTORC1, rendering the later active. The upregulation of mTORC1 activity inhibits autophagy. In a state of hypoxia, HIF-1α is stabilized by the activation of PI3K/Akt. HIF-1α upregulates the expression of glycolytic enzymes and glucose transporters contributing to inflammation-induced glycolysis. Activation of TLR4 also stimulates the proinflammatory JNK pathway, which, along with IKK, phosphorylates the IRS on inhibitory sites. (Created with BioRender.com on 19 October 2022). Abbreviations: LPS, lipopolysaccharide; SFAs, saturated fatty acids; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation factor 88; IRAK1/4, IL-1 receptor-associated kinase 1 and 4; TRAF6, tumor necrosis factor receptor associated factor 6; PI3K, phosphoinositide 3-kinase; IKK, IκB kinase; IκB, inhibitor κB kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; TSC1/2, tuberous sclerosis protein complex 1 and 2; mTORC1, mammalian target of rapamycin complex; HIF-α, hypoxia-inducible factor 1-α; GLUT1, glucose transporter type 1; IR, insulin receptor; IRS, Insulin receptor substrate, JNK, Jun N-terminal kinase; AP-1, activator protein-1.
Figure 3
Figure 3
The Macrophage–Adipocyte Crosstalk in Metabolically challenged Adipose Tissue. Activation of macrophage TLR4 by SFAs induces the expression of proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Binding of proinflammatory cytokines to their corresponding receptors on adipocytes induces the expression of SOCS3 and activates JNK and mTORC1. Stimulation of SOCS3 leads to proteasomal degradation of IRS1. Activated JNK and mTORC1 block IRS1 downstream signaling by promoting phosphorylation of inhibitory serine residues on IRS1. The concomitant insulin signaling inhibition promotes the establishment of insulin resistance in the AT. (Created with BioRender.com on 19 October 2022). Abbreviations: SFAs, saturated fatty acids; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation factor 88; IRAK1/4, IL-1 receptor-associated kinase 1 and 4; TRAF6, tumor necrosis factor receptor associated factor 6; IKK, IκB kinase; IκB, inhibitor κB kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; TSC1/2, tuberous sclerosis protein complex 1 and 2; mTORC1, mammalian target of rapamycin complex; GLUT4, glucose transporter type 4; IR, insulin receptor; IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase; JNK, Jun N-terminal kinase; SOCS3, suppressor of cytokine signaling 3; IL-1β, interleukin 1β; IL-6, interleukin 6; TNF-α, tumor necrosis factor α; CR, cytokine receptor; AT, adipose tissue.
Figure 4
Figure 4
Graphical Summary: Macrophage–Adipocyte Crosstalk in Obese Adipose Tissue. SFAs promote the activation of macrophage NF-κB, which, along with the active inflammasome, induces the secretion of proinflammatory cytokines. These cytokines disrupt adipocyte insulin signaling by inhibiting the IRS1-PI3K/AKT pathway. (Created with BioRender.com on 20 November 2022) Abbreviations: SFAs, saturated fatty acids; TLR4, Toll-like receptor 4; IKK, IκB kinase; IκB, inhibitor κB kinase; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; TSC1/2, tuberous sclerosis protein complex 1 and 2; mTORC1, mammalian target of rapamycin complex; IR, insulin receptor; IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase; JNK, Jun N-terminal kinase; SOCS3, suppressor of cytokine signaling 3; IL-1β, interleukin 1β; IL-6, interleukin 6; TNF-α, tumor necrosis factor α; CR, cytokine receptor.
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