Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis

Green, Courtney R.; Wallace, Martina; Divakaruni, Ajit S.; Phillips, Susan A.; Murphy, Anne N.; Ciaraldi, Theodore P.; Metallo, Christian M.

doi:10.1038/nchembio.1961

Cited by 360 publications

(364 citation statements)

References 50 publications

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“…S2, G–I). This is consistent with recent work demonstrating minimal catabolism of BCAAs to TCA intermediates in proliferating cells (22). We then explored whether excess KIC may be excreted by NSCLC tumors for further metabolism by other tissues such as liver, which has limited Bcat, but high Bckdh activity (21, 23).…”

Section: Main Textsupporting

confidence: 93%

Tissue of origin dictates branched-chain amino acid metabolism in mutantKras-driven cancers

Mayers

Torrence

Danai

et al. 2016

Science

473

445

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Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non-small cell lung carcinoma (NSCLC) respectively, but despite the same initiating events, these tumors utilize branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source while PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA utilization, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue-of-origin is an important determinant of how cancers satisfy their metabolic requirements.

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Section: Main Textsupporting

confidence: 93%

Tissue of origin dictates branched-chain amino acid metabolism in mutantKras-driven cancers

Mayers

Torrence

Danai

et al. 2016

Science

473

445

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“…10 Interestingly, quite recently, isotope studies in adipocytes demonstrated that BCAA catabolism improves adipocyte differentiation. 43 With decreased BCAA catabolism in obesity, SAT may fail to enlarge adequately, 43 which in turn may favour deposition of ectopic fat and subsequent effects on insulin sensitivity. 44 Thus, our study provides a mechanistic link (reduction in mitochondrial catabolism of BCAAs) for the association between circulating BCAA and the risk of T2DM.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity

et al. 2017

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BACKGROUND: Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the wholegenome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics. METHODS: We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n = 26, intra-pair difference in BMI 43 kg m − 2 , aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines. RESULTS: We found 2108 genes differentially expressed (false discovery rate (FDR)o 0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P o 0.05) and upregulation of inflammation pathways (P o 0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR o 0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P o 0.05). CONCLUSIONS: This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

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“…In this sense, AMA protein had the ability to maintain the CHO and TG at the same levels of Ctrl diets (Table 3) while SOY treatment produced a rise of CHO and TG levels and the only difference between the AMA and SOY protein isolates is their amino acid composition. Gorinstein et al [32] reported that SOY has a higher content of branched chain amino acids (BCAAs) such as leucine, isoleucine, and valine and recent reports have shown that BCAAs have an important role in adipocyte metabolism, which could impact in lipogenesis and adipose tissue accumulation, as well as in type 2 diabetes [33,34]. Moreover, it is well known that amaranth proteins contains a better balance of essential amino acids, especially amaranth globulins contains higher amount methionine than soybean proteins.…”

Section: Discussionmentioning

confidence: 99%

Amaranth Protein Improves Lipid Profile and Insulin Resistance in a Diet-induced Obese Mice Model

Escobedo-Moratilla¹,

Velarde‐Salcedo²,

Magaña-Hernández³

et al. 2017

JFNR

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Amaranth has been claimed as functional food, but its function on obesity-related disorder is not fully known. The aim of this study was to analyse the effect of amaranth protein intake on blood lipids profile and insulin resistance in diet-induced obese mice. The effect of soybean protein was also analysed for comparative purposes. C57BL-6 mice were fed for eight weeks with regular or high fat diet. Amaranth or soybean protein isolates (10 mg/kg) were supplied via oral administration. Changes in body weight, adipose tissue, total cholesterol, triglycerides, insulin, a glucose tolerance test, as well as the expression of lipid metabolism-related genes were measured. Our results have shown that amaranth protein induces a decrease in plasma insulin in mice fed with a regular diet, whereas a decrease in triglycerides was observed in mice fed with high fat diet. Furthermore, down-regulation of Tnf-α and Res, suggested the inhibition of inflammation state. The present study demonstrates that amaranth protein, but not soybean protein, improves the obese mice health, and the hormonal modulation (Lep, Fasn, Lpl) could lead to new mechanism of action by which amaranth consumption exerts its beneficial health effect.

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Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis

Cited by 360 publications

References 50 publications

Tissue of origin dictates branched-chain amino acid metabolism in mutantKras-driven cancers

Tissue of origin dictates branched-chain amino acid metabolism in mutantKras-driven cancers

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity

Amaranth Protein Improves Lipid Profile and Insulin Resistance in a Diet-induced Obese Mice Model

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