Last modified on 7 December 2012, at 12:28

Structural Biochemistry/Cell Signaling Pathways/cJun-NH2 Terminal Kinase

File:CJun-NH2 Terminal Kinases Structure.png
CJun-NH2 Terminal Kinases is shown in the above.

cJun N-Terminal Kinase (JNKs)Edit

The cJun N-Terminal Kinase (JNKs) is kinases that are associated with Mitogen-Activated protein kinase and responsible for activation of insulin resistance and responses to stress like ultraviolet irradiation, heat irritation, shocks in osmosis process. The cJun NH2 terminal kinase isoforms JNK1 is associated with cause of activating insulin resistance, which eventually results in obesity in physical body. According to the scientists who have analyzed the physical effect of JNK in genes, JNK on insulin can be differed from it on obesity. JNK1 can affect regulation of insulin resistance such as gene expression, cytokine production, and lipid metabolism. [1]

Insulin Resistance of JNK1-signalsEdit

JNK1 is responsible for insulin resistance that can cause lacking insulin-obesity, which results in diabetes. Risk factors of JNK1 signaling activation in body can cause serious obesity, such as sedentary lifestyle and diet, are seen as major threats to human health since early 2000s. [2]

Due to the activation of JNK1, obesity can be occurred in physical body that can grow into diabetes, a chronic disease in which blood contains excess amount of sugar, causing health-threatening symptoms, such as blindness, damage in nerves, pains in skins and organs, and weight loss. The JNK signaling protein groups can be encoded by JNK1, JNK2 ubiquitously and JNK3 limitedly. Out of all three JNKs, chronic JNK1 has been responsible for activating its own signaling that can be a direct cause of insulin resistance. Such somatic relation between JNK1 Signaling and Obesity-Insulin Resistance can contributed to development and improvement of drug industries, giving an insight of JNK1's mechanism in human bodies.

The regulation of JNK1 on insulin resistance can be taken at the level of resistance to HFD-induced obesity. It is concluded that JNK1 can contribute to HDF-induced insulin resistance regardless of obesity effects on human bodies. Therefore, excess of amount of JNK1 activation can cause obesity and diabetes; yet, in some case, JNK1 can be independent of obesity in body. For example, scientists have concluded that feeding mice with HFD (high fat diet) that have deficient amount of JNK1 can still cause obesity with its normal level consumption on cells and can shows increasing reactivity on insulin compared to controlled mice in the experiment.[3]

The Role of JNK1 in AdipocytesEdit

Adipose tissue, JNK1 controls insulin resistance in cell, especially adipocytes. Adipose tissue takes an essential role in storing fuel of molecules in cell. JNK1 in adipocytes cause knockdown of JNK expression in adipocytes in vitro. [4] IRS phosphorylation can contributed to increasing reactivity of insulin resistance within JNK1 signals. JNK1-deficiency in adipocytes implicated to failure of witnessing increasing expression of Adipokin Interleukin 6 (IL6) in blood when human are fed with HFD. IL6 is responsible for hepatic insulin resistance by increasing adapter protein, SOCS3, which can contributed to degradation in the adipocytes. IL6 can be an important role in meditating insulin signaling in the brain. Increasing the concentration of IL6 in the blood can increase diabetic tissues and causes sensitivity of hepatic insulin in the system. [5]

JNK1 in adipocytes stimulates the IL6 that affects the SOCS3 to activate insulin resistance. Therefore, JNK1 can be independently affect the insulin resistance directly or can affect it dependently via IL6 and SOCS3. The following picture in the left clearly shows that JNK in adiopcytes can act either way to cause insulin resistance in human bodies.

The Role of JNK1 in MuscleEdit

Adipose tissue is not the only site for storage of energy; skeletal muscle tissue also participates in the regulation of glucose levels and insulin sensitivity. Muscle can thus also be where JNK1 resides. An experiment where mice with JNK1-deficient muscle and control mice were fed a HFD was conducted to test this hypothesis. Results showed that the mice suffered from similar forms of obesity; although the muscle tissue of variable mice were protected against insulin resistance, adipose tissue was not. The reasoning behind this protection against HFD-induced insulin resistance is undetermined, but may be attributed to a decrease in IRS1 phosphorylation, also seen in the experiment on mice with JNK1-deficient adipocytes.

Mice with JNK1-deficient muscle tissue experience an increase in the concentration of triglycerides in the bloodstream. A decreased concentration of muscle lipoprotein lipase (LPL) also contributes to increased amounts of triglyceride in the blood while sending some triglyceride to non-muscle tissue. Redistribution of triglycerides to other tissues results in disorders such as hepatic steatosis (liver disease) and adipose tissue inflammation, as well as an increase in insulin sensitivity in muscle tissue and a decrease in insulin sensitivity in tissue receiving the triglycerides. This leads to the conclusion that LPL-deficiency may be a contributing factor to the protection against insulin resistance in muscle JNK1-deficient mice. [6]

The Role of JNK1 in the LiverEdit

The liver plays a key role in regulating a wide range of homeostatic processes, including glucose homeostasis. It is therefore a candidate for regulation by JNK1. However, studies show that JNK1 in the liver does not contribute to insulin resistance; in fact, the opposite occurs. Mice with JNK1-deficient liver tissue experience insulin resistance when fed a HFD. [7]

The Role of JNK1 in the Central Nervous SystemEdit

Since the hypothalamus is responsible for regulation of food intake and physical activity, the central nervous system is a strong candidate for regulation by JNK1. An experiment was conducted where mice with JNK1-deficiency in the nervous system were fed a HFD. Results showed that removal of JNK1 from the nervous system helped prevent obesity and increased insulin sensitivity. The hypothalamus reacted to the HFD by decreasing food intake and increasing physical activity. However, JNK1-deficiency in the nervous system led to a change in hormone levels regulated by the hypothalamic-pituitary-thyroid axis. Such changes may be a contributing factor to resistance against HFD-induced obesity. In conclusion, mice with JNK1-deficient nervous systems are protected against obesity and insulin resistance due to responses regulated by the hypothalamus. [8]

Diet-induced JNK1 ActivationEdit

To activate JNK1 in Insulin tissues, such as muscle, liver and fat, addition of HFD (High Fat Diet) should be applied in human.[9] Mitogen-activated protein kinase kinases (MMK4 and MKK7) activates JNK1. Four main mechanisms for JNK1 activation to be processed: 1) exposure of cell to fatty acids (lipids); thus results in stress in ER (Endoplasmic Reticulum) of protein response pathway to JNK1 activation, 2) saturated fatty acids acts as ligands in cell structures that activates JNK pathway, 3) Fatty acids also activates the JNK pathway by protein kinase C-mediated activation that is medicated by proteins, and 4) High Fat Diet-induced insulin resistance is implicated with low expression of inflammatory cytokines---causing activation of JNK, including necrosis of tumor.

JNK1 in MacrophagesEdit

During the development of insulin resistance on human body, JNK1 in macrophages can influences on the absorption of adipose tissue by macrophages in cells and also can alter the inflammatory cytokines such as tumor necrosis factors. Two main roles of JNK1 in macrophages are following: 1) Transplantation of bone marrows in skeletal tissues can be contributed by JNK deficient hematopoietic system; surprisingly, in this case, the system is independent from HFD-induced insulin resistance. [10]
2) Insulin resistance is independent of containment of JNK1 in cell. For example, both controlled mice with JNK1-deficiency can have insulin resistance in their bodies.[11]