Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance

Abstract

Obesity induced low-grade inflammation (metaflammation) impairs insulin receptor signaling (IRS). This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), inhibitor of NF-kB kinase complex beta (IKKβ), AMP activated protein kinase (AMPK), protein kinase C (PKC), Rho associated coiled-coil containing protein kinase (ROCK) and RNA-activated protein kinase (PKR), etc. Most of these kinases phosphorylate several key regulators in glucose homeostasis. The phosphorylation of serine residues in the insulin receptor (IR) and IRS-1 molecule results in diminished enzymatic activity in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This has been one of the key mechanisms observed in the tissues that are implicated in insulin resistance especially in Type II Diabetes Mellitus (T2-DM). Identifying the specific protein kinases involved in obesity induced chronic inflammation may help in developing the targeted drug therapies to minimize the insulin resistance. This review is focused on the protein kinases involved in the inflammatory cascade and molecular mechanisms and their downstream targets with special reference to obesity induced T2-DM.

A novel berberine‐metformin hybrid compound exerts therapeutic effects on obese type 2 diabetic rats

“…Besides, G6Pase , FBPase and PEPCK genes are responsible for gluconeogenesis. It has been well established that the downregulation of G6Pase , FBPase and PEPCK genes can significantly inhibit gluconeogenesis, and subsequent reduce blood glucose levels . In the present study, BMH473 inhibited hepatic steatosis and reduced hepatic lipid contents in obese T2DM rats, by regulating the protein expressions of PPAR‐α and SREBP‐1 c, as well as the mRNA expressions of LDLR , FAS and Scd 1 .…”

“…Inflammation in WAT is one of the common pathological changes in obese T2DM rats. Inflammatory pathways have been increasingly recognized as novel factors contributed to the development of T2DM, especially insulin resistance . Several studies have demonstrated the elevated levels of pro‐inflammatory cytokines (TNF‐α, IL‐1 β and IL‐6) in obesity and T2DM .…”

Pre-germinated brown rice extract ameliorates high-fat diet-induced metabolic syndrome

“…Hyperglycemia and insulin resistance cause cells to lose insulin sensitivity and inhibit their ability to uptake glucose. The IR, with the signal increasing through a cascade of molecules (PI3K/Akt signaling pathway), is deteriorated by hyperglycemia and insulin resistance, which worsens the ability of GLUT to facilitate glucose uptake into the cells (Babu, Liu, & Gilbert, ; Nandipati et al, ; Oliveira et al, ) In this study, the HFD reduced the protein expressions of AMPK, IR, IRS‐1, IRS‐2, PI3K, Akt/PKB, GLUT‐1, and GLUT‐4 (Figure ). Although the insulin level increased, the proteins related to glucose uptake were impaired and the fasting blood glucose, HbA1c, and OGTT levels were higher in the HFD group compared to the RD group (Table ).…”

Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism

“…p38 MAPKs are stress-responsive MAPKs that are activated by a variety of stresses in addition to cytokines and growth factors [10, 32, 33]. The p38 MAPK signaling module consists of MAPKKK-MKK3/4/6-p38MAPK [10].…”