Coordinated Modulation of Energy Metabolism and Inflammation by Branched-Chain Amino Acids and Fatty Acids

Abstract

As important metabolic substrates, branched-chain amino acids (BCAAs) and fatty acids (FAs) participate in many significant physiological processes, such as mitochondrial biogenesis, energy metabolism, and inflammation, along with intermediate metabolites generated in their catabolism. The increased levels of BCAAs and fatty acids can lead to mitochondrial dysfunction by altering mitochondrial biogenesis and adenosine triphosphate (ATP) production and interfering with glycolysis, fatty acid oxidation, the tricarboxylic acid cycle (TCA) cycle, and oxidative phosphorylation. BCAAs can directly activate the mammalian target of rapamycin (mTOR) signaling pathway to induce insulin resistance, or function together with fatty acids. In addition, elevated levels of BCAAs and fatty acids can activate the canonical nuclear factor-κB (NF-κB) signaling pathway and inflammasome and regulate mitochondrial dysfunction and metabolic disorders through upregulated inflammatory signals. This review provides a comprehensive summary of the mechanisms through which BCAAs and fatty acids modulate energy metabolism, insulin sensitivity, and inflammation synergistically.

Keywords: branched-amino acids; energy metabolism; fatty acids; inflammation; insulin resistance; mitochondrial biogenesis.

Figure 1

Catabolism pathways of branched-chain amino acids and fatty acids. Various intermediate metabolites produced by the catabolism of BCAAs and fatty acids can participate in the TCA cycle and glycolysis. The catabolism of BCAAs and fatty acids can interplay through these metabolites and ultimately impact the production of mitochondrial ATP through the electronic transport chain. The catabolism of BCAAs in the mitochondria is shown on the left, while the catabolism of fatty acids in cytoplasm and mitochondria is shown on the right. The dotted line indicates a multistep reaction, and the solid line indicates a one-step reaction. DHAP, dihydroxyacetone phosphate; 3-HIB, 3-hydroxyisobuterate; HIBCH, 3-hydroxyisobutyryl-coenzyme A hydrolase.

Figure 2

Mechanism of BCAAs and fatty acids regulating energy metabolism. BCAAs and fatty acids affect mitochondrial energy metabolism through different mechanisms in different cells. In mouse heart perfusate, BCAAs inhibited the activity of pyruvate dehydrogenase. In muscle cells, the increased citrate inhibits the accumulation of phosphofructokinase and glucose-6-phosphate. In liver cells, BCKAs can directly suppress the expression of respiratory complex II/SDH to reduce the production of ATP. In the figure, the dotted line indicates a multistep reaction, and the solid line indicates a one-step reaction. SDH, succinate dehydrogenase.

Figure 3

Mechanism of BCAAs and fatty acids regulating inflammatory signals. BCAAs and different types of fatty acids regulate the inflammatory response through the NF-κB pathway and NLRP3. SFAs, saturated fatty acids; UFAs, unsaturated fatty acids; TXNIP, thioredoxin-interacting protein.

Figure 4

Effects of BCAAs and fatty acids on insulin signal transduction. Under normal circumstances, insulin can activate various molecules such as PI3K, Akt, and mTOR to affect the activation of IRS and regulate the transport and ectopic expression of GLUTs. Increased levels of BCAAs and fatty acids can interfere with normal insulin signaling through various mechanisms and ultimately lead to IR. In the figure, the dotted line indicates a multistep reaction, and the solid line indicates a one-step reaction.