Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
Highlights
The first major link made between inflammation and obesity identified the pro-inflammatory cytokine tumor necrosis factor α (TNFα): tissues obtained from obese humans, as well as the adipose from murine models of obesity, had elevated
Several in vitro studies using the 3T3-L1 adipocyte cell line concluded that jun N-terminal kinase (JNK) plays a role in mediating free fatty acids (FFA)-induced insulin resistance, and inhibiting JNK has beneficial effects in restoring insulin sensitivity [84,85]
IL-6 was the only pro-inflammatory cytokine found to be elevated in wildtype (WT) mice on high-fat diet (HFD), compared to adipocyte-specific JNK1-null mice on HFD, and its administration in these JNK1-null mice abolished their protection from HFD-induced hepatic insulin resistance [86]
Summary
The prevalence of obesity has substantially increased in the past few decades, being described as a global epidemic. Appropriate cellular response [13] By having this step-by-step progression, various signals can an be MAP2K will Thr/Tyr phosphorylate and activate MAPK, effectively transmitting integrated intosignal cellular responses, which can provide regulation, wellstep-by-step as points of extracellular into an appropriate cellular multiple responsepoints [13].ofBy having as this crosstalk with other signaling pathways within the cell [11]. For. Specific to the JNK pathway, TAK1, MEKK1, MEKK4, ASK1, and MLK are all considered MAP3Ks, as these kinases are first to respond to various inputs that eventually activate JNK. Some of the MAP3Ks mentioned above preferentially activate MKK4, while others activate MKK7 These kinases phosphorylate JNK on Tyr185 and Thr183 respectively to activate it [13]. It is still unclear as to how MKK4 is activated in the context of cytokine exposure; one possibility lies in the fact that PKC-induced phosphorylation of JNK may sensitize JNK to MKK4/7 action [17]
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