Figure 2

Schematic representation of forward (solid arrows) and backward (broken arrows) mechanism underlying MIR, as discussed. By the forward mechanism, imcTG is at a hyperdynamic state characterized by accelerated synthesis (Syn, ref. 21) and turnover (TO, ref. 31) in the earlier stages of metabolic complications such as obesity. This increases the flux and availability of intramyocellular fatty acids (FA/LCFA), DAG, LCACoA and ceramides and thus signaling via PKC system, and promotes mitochondrial β-oxidation (β). As a result, PI3K is inhibited and GLUT4 translocation impaired resulting in reduced insulin-mediated glucose uptake (MIR). Over time, the overloading of mitochondria by β-oxidation gradually causes mitochondrial damages and dysfunctions (MD) via mechanisms such as oxidative stress and DNA damage. When this occurs, mitochondrial β-oxidation reduces. At this stage (e.g. T2D or advanced aging), the backward mechanism prevails. The decline in fatty acid oxidation causes imcTG to accumulate. Gray-scaled mitochondria (mito) represents damaged mitochondria. The thickness of arrows approximates the sizes of the fluxes.