There is no fattening like fattening, try super fattening with vegetable oils (activate NOX2)!

We have already shown here that the problem arises when fat cells "get wild" and stop listening to external signals, turn on hypoxia, activate HIF-1α and turn on fat formation (lipogenesis). The triggering of this state is activated by excess fuel, lack of oxygen, excess hydrogen peroxide, lack of glutathione and mainly by the activity of the enzyme DECR, which metabolizes polyunsaturated fats, especially omega-6 with unsaturated bonds in even positions, and pathologically reduces metabolic insulin resistance.

Activation of NADPH oxidase (NOX) and signaling by hydrogen peroxide (H2O2).

We also showed that NOX enzymes, which create hydrogen peroxide on the outside of the cell membrane, let glucose into cells just like insulin. If this activity is only short-term, it is part of normal regulatory mechanisms. However, long-term activation is very bad, continuous production of H2O2 not only enhances catalase activity, it also leads to the degradation of polyunsaturated fats in cell and mitochondrial membranes. These peroxidized fats (e.g. HPODE) can permanently activate the production of catalase, but they are not, unlike H2O2 , disposed by it. And the increased level of extracellular catalase is behind the disobedience of the cells, erasing external signals mediated by H2O2 molecules.

Both hydrogen peroxide and peroxidized omega-6 oils activate catalase.

Catalase terminates the activity of H2O2 but does not terminate the activity of omega-6 peroxidized oils (HpODE). Permanent activation occurs.

The activity of the enzyme NADPH oxidase 2 (NOX2) appears to be an important auxiliary factor for the activation of pseudohypoxia, i.e. the activation of HIF-1. Let's see how the genetic deactivation of the NOX2 enzyme affects mice. A high-fat diet accelerates weight gain. The experiment always includes a diet containing enough omega-6 vegetable oils. This leads to an overload of the fat cell with fuel, insufficient metabolic insulin resistance ensures pathological obesity, which is mediated, among other things, by the activation of NOX enzymes. Genetic or chemical inactivation of NOX2 has a protective effect similar to MCT oil or flavonols, HIF-1 is not activated. Although a fatty diet always causes obesity, if functional regulatory mechanisms are maintained, the sensitivity of insulin receptors (pAKT) and the vasodilatory function of the eNOS enzyme will be preserved. NOX2 and HIF-1 activity are mutually reinforcing, the positive feedback acting as a metabolic switch. In addition, activation of HIF-1 and NOX2 increases LDL cholesterol, free fatty acids (FFA), and blood pressure (Systolic BP). This should be avoided, preferably by eliminating all vegetable omega-6 oils.

Weight of mice on a normal diet (NCD), on a high-fat diet with NOX2 activated by omega-6 oils (HFD), on the same high-fat diet with NOX2 chemically inactivated (HFD+apo) and NOX2 genetically inactivated (Nox2KO).

Note that when the NOX2 enzyme is turned off, insulin receptor sensitivity (P-Akt) and endothelial nitric oxide production (P-eNOS) are preserved even with a high-fat diet.

Strong antioxidants such as N-acetyl cysteine (NAC) or vitamin E can essentially also suppress NOX2-induced HIF-1α activation. But it is a double-edged sword, the signal of self-destruction (apoptosis) is also suppressed, so depending on the situation, they can also support the growth of tumors. NOX2 activity in vascular endothelial cells suppresses vasodilation, i.e. the function of nitric oxide and nitrite. This brings us back to the theory of aging as progressive pseudohypoxia, i.e. gradually increasing NOX2 activity (via HIF-1 activation). This can also explain the gradual loss of activity of the endothelial enzyme synthesizing nitric oxide, i.e. eNOS, as we have shown here.