III.2.B.h. Tumor necrosis factor-alpha (TNF-α)

Its main effects:        

It inhibits signalization through the insulin receptor, causes insulin resistance in the adipocytes, and increases FFA release.

Insulin resistance is diminished by inhibition of the TNF-α receptor in mice, but this was not found in humans. 

It increases the death of adipocytes (apoptosis), and enhances cholesterol and FFA synthesis and lipolysis. 

It decreases the amount of the GLUT-4 Glu transporter, which leads to the decrease of Glu uptake.

It influences the endothelial function, and increases the synthesis of adhesion molecules.

It increases the synthesis of endothelin-1 (ET-1), which activates matrix metalloproteinases, leading to vasoconstriction and the formation of atherosclerotic plaque. 

It increases the IL-6 level.

It decreases the levels of adiponectin and HDL.  

It enhances the amounts of oxidized LDL receptors and monocytes, and thereby has a role in atherosclerosis induction. 

Its expression is regulated by angiotensin-II (A-II).

Its expression is inhibited by PPAR-α, angiotensin-I-converting enzyme (ACE), angiotensin II receptor blockers (ARB) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR, which stimulates the initial steps of the formation of terpenes and steroids synthesized from acetyl coenzyme A); these molecules therefore have cardio-protective effects.

An increase in its level leads to damage of the pancreatic β-cells (insulin-releasing cells).

Its level correlates well with the BMI, the percentage of body fat mass, the body weight, the waist circumference and the TG and plasma insulin levels.