Inflammation and ER Stress Regulate Branched-Chain Amino Acid Uptake and Metabolism in Adipocytes

Abstract

Inflammation plays a critical role in the pathology of obesity-linked insulin resistance and is mechanistically linked to the effects of macrophage-derived cytokines on adipocyte energy metabolism, particularly that of the mitochondrial branched-chain amino acid (BCAA) and tricarboxylic acid (TCA) pathways. To address the role of inflammation on energy metabolism in adipocytes, we used high fat-fed C57BL/6J mice and lean controls and measured the down-regulation of genes linked to BCAA and TCA cycle metabolism selectively in visceral but not in subcutaneous adipose tissue, brown fat, liver, or muscle. Using 3T3-L1 cells, TNFα, and other proinflammatory cytokine treatments reduced the expression of the genes linked to BCAA transport and oxidation. Consistent with this, [(14)C]-leucine uptake and conversion to triglycerides was markedly attenuated in TNFα-treated adipocytes, whereas the conversion to protein was relatively unaffected. Because inflammatory cytokines lead to the induction of endoplasmic reticulum stress, we evaluated the effects of tunicamycin or thapsigargin treatment of 3T3-L1 cells and measured a similar down-regulation in the BCAA/TCA cycle pathway. Moreover, transgenic mice overexpressing X-box binding protein 1 in adipocytes similarly down-regulated genes of BCAA and TCA metabolism in vivo. These results indicate that inflammation and endoplasmic reticulum stress attenuate lipogenesis in visceral adipose depots by down-regulating the BCAA/TCA metabolism pathway and are consistent with a model whereby the accumulation of serum BCAA in the obese insulin-resistant state is linked to adipose inflammation.

Time-course changes in circulating branched-chain amino acid levels and metabolism in obese Yucatan minipig

“…However, the phosphorylation of the BCKDH complex was increased only in SCAT, suggesting a reduced oxidative capacity. In contrast to what has been described in rodents [23], the present results suggest for the first time the existence of a SCAT-specific regulation. This discordance with other species might be explained by the fact that in humans, increased VAT deposition is associated with an increased risk for IR and although SCAT is associated with improved or preserved insulin sensitivity, and mitigated risk for developing type 2 diabetes and other metabolic derangements [24].…”

Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice

“…In line with this, we have reported increased expression of genes that are associated with mitochondrial branched-chain amino acid (BCAA) cycle such as Bckdha and Bcat2 , and citric acid or tricarboxylic acid (TCA) cycle such as Cs and Pdha1 with concomitant increase in leucine and pyruvate oxidation in Cpt1b m−/− muscle23. Previous studies have indicated that higher levels of TNFα are associated with decreased expression of BCAA/TCA cycle genes70. The lower levels of TNFα expression reported in our study are therefore consistent with the observed enhanced expression of BCAA and TCA cycle genes in Cpt1b m−/− mice.…”

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

“…Furthermore, supplementing high fat diet with BCAAs induced insulin resistance despite reduced food intake and weight gain, and was associated with increased activity of JNK in muscle (Newgard et al, 2009). Interestingly, a recent report showed that exposure to inflammatory cytokines blocked the uptake and metabolism of BCAAs in adipocytes, which could underlie the elevated levels observed in obese patients (Burrill et al, 2015). In addition, exposure to the macromolecules synthesized by pathogenic and commensal species can also have marked immunomodulatory and metabolic consequences.…”