The PI3K/Akt Pathway in Meta-Inflammation

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.

The Prebiotic Effects of an Extract with Antioxidant Properties from Morus alba L. Contribute to Ameliorate High-Fat Diet-Induced Obesity in Mice

“…Since the obesity-associated oxidative stress contributes to the development of the characteristic subclinical inflammatory response, the expression of different proinflammatory markers was determined in fat and liver tissues. In epididymal fat, the expression levels of p38, AKT and COX-2 were determined, being these proteins closely related to the inflammatory response that occurs in obesity [ 28 , 29 , 30 ]. While metformin administration promoted a significant reduction in protein levels for MAPK and AKT, the extract showed a trend to reduce them, showing no statistical differences when compared to non-obese mice ( Figure 5 B,C).…”

“…In adipose tissue, the activation of this signaling cascade results in the promotion of lipid biosynthesis and the suppression of lipolysis. Therefore, activated AKT contributes to an increase in fat deposits [ 29 ]. Additionally, it has been reported that insulin resistance may result in overactivation of the PI3K/AKT pathway [ 52 ].…”

Dietary Evodiamine Inhibits Atherosclerosis-Associated Changes in Vascular Smooth Muscle Cells

“…In other diseases, such as pancreatic cancer, the PI3K/Akt axis is the upstream signaling pathway through which evodiamine modulates cellular activity [ 43 ]. Moreover, studies have also confirmed that the PI3K/Akt axis is involved in the regulation of inflammatory response and oxidative stress [ 44 , 45 , 46 ]. Following evodiamine treatment, p-PI3K and p-Akt protein levels decreased in vitro.…”

Changes in Lipid Metabolism Enzymes in Rat Epididymal Fat after Chronic Central Leptin Infusion Are Related to Alterations in Inflammation and Insulin Signaling

“…Direct actions of leptin on cell metabolism are rather unusual, and are mainly mediated by its effects on insulin sensitivity in adipocytes [ 8 ]. We found a reduction in the phosphorylation of the insulin receptor and downstream targets of this pathway in the epididymal fat of pair-fed and leptin-infused rats, which was more significant in the latter group, and this inhibited insulin’s actions in adipocytes [ 44 ]. In addition, JNK activation in leptin-infused rats could interfere with insulin signaling by increasing IRS1 degradation and triggering IRS1 serine phosphorylation in fat, thus lessening the signaling and promoting inflammation [ 45 ].…”