Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling

Abstract

Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1and mTORC2-dependent pathways. BCAAs/branchedchain a-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/ BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.

Postprandial NMR-Based Metabolic Exchanges Reflect Impaired Phenotypic Flexibility across Splanchnic Organs in the Obese Yucatan Mini-Pig

“…Thus, the increased postprandial uptake of BCAA after two months of HFHS feeding could respond to the increased circulating concentration of BCAA already observed in obese hyperinsulinemic mini-pigs [ 5 , 52 ]. Indeed, high insulin levels have been shown to enhance BCAA uptake in the liver of obese rats [ 53 ] and promote further severe liver insulin resistance by the attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways [ 54 ].…”

Dairy consumption and hepatocellular carcinoma risk

“…Patients with high BCAT1 expression possess a lower overall survival than those with low BCAT1 expression (103). Leucine and its conversion product α-ketoisocaproate (KIC) are sensed by leucyl-tRNA synthase (LeuRS) (Figure 1) (104). LeuRS acts as a GTPase-activating protein (GAP) for RagD GTPase activating mTORC1 (105).…”

“…LeuRS acts as a GTPase-activating protein (GAP) for RagD GTPase activating mTORC1 (105). In high fat-diet (HFD)-treated diet-induced obesity (DIO) mice, BCAA supplementation increased hepatic BCAA and BCKA levels and induced severe hepatic insulin resistance (IR) (104).…”

Targeted Metabolomics Identifies Differential Serum and Liver Amino Acids Biomarkers in Rats with Alcoholic Liver Disease

“…The decrease of BCAAs in ALD also indicates that alcohol may cause a deficiency of nutrient intake (19). Zhao et al (25) found that BCAAs exacerbated obesity-related hepatic glucose and lipid metabolic disorders through attenuating Akt2 signaling. Tedesco et al (26) found that enriched in BCAAs reverted these molecular defects and mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway.…”