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. 2022 Jul 18;10:945287. doi: 10.3389/fcell.2022.945287

FIGURE 3.

FIGURE 3

The diagrammatic illustration of the adipogenic role of fetuin-A. Excess fetuin-A release (from liver and adipocytes) may increase FFA uptake and accumulation in adipocytes and impair their function by inhibiting PPARγ and stimulating mTOR. Fetuin-A-mediated inhibition of PPARγ occurs through phosphorylation at serine 273 by TLR4-induced activation of NFκB-TNFα-Ras-MEK-ERK cascading. This suppression of PPARy lowers adiponectin levels and antagonizes its insulin-sensitizing and anti-inflammatory actions by impairing AMPK and mitochondrial bioenergetics. Besides, inhibition of PPARy downregulates the expression of CD36, resulting in lipogenesis and excess fat accumulations in adipocytes, disrupting insulin sensitivity. Excess fetuin-A also plays builds up excess fat in the liver and adipocytes by the stimulatory phosphorylation of mTOR that enhances the expression of SREBP-1c inducing lipogenesis. Ultimately, fetuin-A-induced disruption of mitochondrial bioenergetics and increased lipogenesis results in hepatic steatosis, NAFLD, IR, and T2DM. Abbreviations: AMPK, AMP-activated kinase; mTOR, phosphorylation of mammalian target of rapamycin; NFκB, nuclear factor κB; PPARy, Peroxisome proliferator-activated receptor-gamma; SREBP-1c, steroid regulatory element-binding protein-1c; TNF-α, tumor necrosis factor-alpha.