Hormonal
In obesity, elevated saturated fatty acids and proinflammatory cytokines activate JNK and IKK kinases, which phosphorylate insulin receptor substrate (IRS) on inhibitory serine residues, thereby blocking PI3K/Akt signaling and causing insulin resistance.
If you have excess body fat, your cells are likely resisting insulin due to inflammatory signaling triggered by fats and cytokines. This isn't permanent damage; it's a reversible signaling block. Reducing caloric excess and saturated fat intake can lower the metabolic stress that triggers this inflammatory kinase activity, potentially restoring insulin sensitivity.
High concentrations of SFAs stimulate TLR4 and as a consequence the proinflammatory pathways JNK and IKK. Both JNK and IKK phosphorylate the serine/threonine residues on IRS proteins (Figure 2). This phosphorylation prevents the IR from interacting with the IRS, blocking the downstream insulin signal transduction, including the PI3K/Akt pathway.
Why this rating
The paper is a review citing multiple primary studies and mouse models, establishing a strong mechanistic consensus.
Source
The PI3K/Akt Pathway in Meta-Inflammation
Maricedes Acosta‐Martínez et al. · International Journal of Molecular Sciences · 2022
DOI 10.3390/ijms232315330
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