Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats

Abstract

Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-13C]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-13C]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart

“…To determine if the robust reamination of KIV to valine applies to other BCKA, we also perfused isolated hearts with αketoisocaproate labeled in the 1-and 2-carbon positions ([1,2-13 C]KIC). Similar to our findings with labeled KIV, perfusion of hearts with [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]KIC resulted in robust labeling of leucine (80.2 ± 4.6%) ( Supplementary Fig. 1a).…”

“…T he association of branched-chain amino acids (BCAA-valine, leucine, isoleucine) and their α-ketoacids (BCKA) with metabolic diseases such as obesity, insulin resistance, and diabetes are now well documented [1][2][3][4] , and mechanisms underlying these associations are beginning to emerge [5][6][7][8] . The role of BCKA metabolism in cardiac health and disease is less well understood.…”

Dietary Energy Partition: The Central Role of Glucose

“…The role of a few amino acids in the maintenance of glycaemia via gluconeogenesis [ 89 , 106 ] is well known, but the focus is now on branched-chain amino acids [ 107 , 108 ]. These amino acids are catabolized to 2C fragments (leucine and isoleucine) and propionate (valine and isoleucine) [ 109 ] (nor a 3C but an important anaplerotic precursor of 4C fragments [ 110 ]).…”

Plasma BCAA concentrations during exercise of varied intensities in young healthy men—the impact of endurance training

“…In addition, Wang et al (2011) found that five circulating branched-chain and aromatic amino acids (including leucine, isoleucine, valine, tyrosine and phenylalanine) might be used as early markers of diabetes risk. On the other hand, restriction of dietary BCAA by lowering of circulating BCAA levels improves whole-body and skeletal muscle insulin sensitivity in obese rats ( White et al, 2016 ) and lowers lipid accumulation in their hearts, which has positive impact on cardiometabolic health ( McGarrah et al, 2020 ) .…”