Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism

Shin, Andrew C.; Faßhauer, M; Filatova, Nika; Grundell, Linus A.; Zieliński, Elizabeth; Zhou, Jian; Scherer, Thomas; Lindtner, Claudia; White, Phillip J.; Lapworth, Amanda L.; Ilkayeva, Olga; Knippschild, Uwe; Wolf, Anna Maria; Scheja, Ludger; Grove, Kevin L.; Smith, Richard; Qian, Weijun; Lynch, Christopher J.; Newgard, Christopher B.; Buettner, Christoph

doi:10.1016/j.cmet.2014.09.003

Cited by 129 publications

(157 citation statements)

References 46 publications

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“…This finding suggests that, in mice, other tissues likely contribute to the changes in BCAA levels. A recent study describes the effects of insulin on hepatic protein levels and activity of BCKDH in controlling BCAA catabolism [30]. Since ob/ ob mice are hyperinsulinaemic, the plasma BCAA concentrations may be influenced more strongly by hepatic BCKDH in ob/ob mice, which is also supported by the strong correlations of plasma α-ketoisocaproic acid and hepatic BCAA in the correlation network of the ob/ob mice.…”

Section: Discussionmentioning

confidence: 92%

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

et al. 2015

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Aims/hypothesis Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetesassociated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. Methods Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semiquantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. Results Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, Ophosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. Conclusions/interpretation By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.

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Section: Discussionmentioning

confidence: 92%

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

et al. 2015

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“…In contrast to the prevailing view that these mice might exhibit metabolic syndrome (62,63), they instead exhibited decreased adiposity and body weight and resistance to diet-induced obesity, even though they ate more food than their wild-type counterparts. In addition, BCATm KO mice exhibited 33% reductions in their plasma glucose levels, a ϳ50% reduction in glucose tolerance test (GTT) areas under the curve along with ϳ50% reductions in plasma insulin during the GTT and improved insulin sensitivity, but not maximal insulin action (76,79). However, these mice also had reduced exercise tolerance (76).…”

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confidence: 99%

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Lynch

Kimball

et al. 2015

Physiological Genomics

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Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics 47: 569-580, 2015. First published September 8, 2015 doi:10.1152/physiolgenomics.00055.2015.-Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, ␣-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and ␣-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wildtype mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/ϳ39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

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“…[53][54][55][56] We have recently revealed for the first time the role of insulin in the regulation of BCAA metabolism by demonstrating that insulin dose-dependently lowers plasma BCAAs independent of glycemia via induction of hepatic BCAA catabolism. 51 We further showed that this control of BCAA metabolism is mediated primarily through insulin action in the brain, and that impaired BCAA metabolism and the resultant higher plasma BCAA levels ensue in a state of central insulin resistance.…”

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confidence: 76%

“…49 Rather, the increased circulating BCAAs and their intermediates may be because of decreased or impaired BCAAs degradation in tissues like liver, muscle, and adipose tissue. This concept of impaired BCAAs metabolism in obesity and diabetes is supported by findings demonstrating decreased gene expressions of BCAA-degrading enzymes in subcutaneous and omental fat tissues in obese twins compared to their lean monozygotic co-twins, 50 decreased protein or activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in BCAA degradation pathway, in livers of obese ob/ob mice and diabetic fa/fa rats, 8 in HFD fed rats and diet-induced obese men and monkeys, 51 as well as in obese Pima Indians. 52 The reasons for dysregulated BCAA metabolism in obese and diabetics are unclear.…”

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confidence: 89%

Are BCAAs Mere Biomarkers of Diabetes?

Shin¹

2017

Diabetes Res Open J

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Branched-chain amino acids (BCAAs; ie. leucine, isoleucine, and valine) are essential amino acids we need to ingest through our diet.While circulating BCAA levels were first found to be elevated in obese individuals back in 1969 by Felig and colleagues, 1 the potential role of BCAAs in obesity and diabetes development has been re-highlighted in the last decade. Using advanced metabolomic platforms, many independent investigators were able to reproduce the earlier finding and further demonstrate that not only plasma BCAAs, but also their partially oxidized intermediates such as α-keto acids and short-chain (C3-C5) acylcarnitines are increased in obese or insulin resistant/diabetic individuals, including Caucasians and Asians. 2-9Moreover, plasma BCAAs are found to be the earliest and the most predictive marker for future risk of diabetes, 10 and elevated plasma leucine levels precede the development of fatty liver, 11suggesting that circulating leucine is a predictive marker of hepatic steatosis. Interestingly, plasma BCAAs and their derived short-chain acylcarnitines are effectively lowered by bariatric surgery in obese and/or diabetic individuals. 5,8,12,13 Whether this normalized BCAA metabolism after RYGB surgery in morbidly obese patients contributes to improved insulin sensitivity and glycemic control or is just a secondary effect of the surgery needs to be examined further. Nonetheless, collectively these studies implicate a role of plasma BCAAs and their metabolites in the pathogenesis of insulin resistance and diabetes.The unresolved question in the field today is whether or not they are mere biomarkers or they are one of the potential culprits for derangement of glucose metabolism and development of obesity and insulin resistance/diabetes. While a number of studies demonstrate that either amino acid mixture or BCAA supplementation have beneficial effects on protein turnover and muscle wasting in patients with cirrhosis, kidney failure, cancer, or sepsis, [14][15][16][17][18][19][20][21][22][23][24][25] mounting evidence suggests that amino acids/BCAAs or their metabolized keto acids lead to hyperactivation of mTOR signaling, 7,26-28 induction of oxidative stress, 29-32 mitochondrial dysfunction, 33,34 apoptosis, 35,36 and more importantly, insulin resistance and/or impaired glucose metabolism. 7,[26][27][28][37][38][39][40][41][42][43][44] Consistent with these findings, recent studies demonstrate that a BCAA metabolite elevated in diabetic individuals can drive vascular fatty acid transport in muscle and induce insulin resistance in mice 44 and a defective muscle BCAA metabolism induces impaired lipid metabolism and insulin resistance.45 On the other hand, deprivation of a single or all three BCAAs improves insulin sensitivity and glycemic control in either chow-or High-Fat Diet (HFD)-fed, or genetically diabetic rodents.46-48 These findings strongly indicate not only a correlative, but also a causative role of circulating BCAAs and their oxidized intermediates in the development of insulin resistance ...

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Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism

Cited by 129 publications

References 46 publications

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Are BCAAs Mere Biomarkers of Diabetes?

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