Branched-chain amino acids (BCAA) are a group of essential amino acids consisting of leucine, isoleucine, and valine. Leucine, in particular, has signaling functions affecting protein and energy metabolism. Plasma leucine concentration is positively correlated with obesity and associated metabolic disorders. We set out to test the hypothesis that metabolic dysfunction from high fat diets precedes dysfunctional BCAA metabolism. First, BCAA were supplemented to neonatal pigs for 4 weeks to evaluate whether the anabolic signaling function of leucine could increase muscle growth when fed for a longer duration than in previous studies. Neither normal pigs nor low birth weight pigs, which have naturally impaired muscle growth, grew better in response to BCAA supplementation, despite low birth weight pigs expressing less of the leucine sensing protein Sestrin2 in skeletal muscle. Furthermore, high plasma BCAA concentrations caused by the experimental diets had no effect on adiposity, liver fat accumulation, or expression of genes related to fatty acid synthesis, mitochondrial biogenesis, or energy expenditure in the pigs' livers. Having produced strong evidence that long term BCAA supplementation neither improves lean growth nor causes abnormal fat metabolism, we then tested whether fat supplementation changes BCAA metabolism. Pigs were fed milk replacer formula with either low energy (Control), or high energy from long-chain fatty acids (LCFA) or medium-chain fatty acids (MCFA) for 22 days. Although high fat diets did not increase plasma BCAA concentrations, the MCFA diet in particular caused metabolic changes which could lead to fatty liver disease and decreased oxidative BCAA disposal. Expression of fatty acid synthesizing genes were increased in the livers of pigs fed MCFA formula compared to Control and LCFA formula. Oxidation of α-ketoisocaproic acid was decreased in liver homogenate of pigs fed MCFA and LCFA formulas compared to Control. Additionally, hepatic oxidation of α-ketoisovalerate was decreased, and plasma concentration of α-ketoisovalerate was consequently increased, in pigs fed MCFA formula compared to Control, with LCFA formula causing intermediate results. In future research, it would be valuable to feed high MCFA formula for a longer period of time to determine whether nonalcoholic fatty liver disease will develop, and whether plasma BCAA concentrations will increase due to decreased oxidation. Overall, these studies concluded that long term BCAA supplementation does not increase muscle growth in neonatal pigs, but there is also no indication that they cause obesity or dysfunctional fat metabolism. On the other hand, high fat diets cause impairments in BCAA catabolism which may precede elevated plasma BCAA concentrations. / Doctor of Philosophy / Branched-chain amino acids (BCAA) are essential amino acids which are abundant in plant and animal proteins. In addition, the BCAA leucine has functions in protein and energy metabolism. Leucine consumption induces a signal to build new muscle protein. However, leucine concentration is also higher in blood plasma of obese individuals than in non-obese individuals, which has caused uncertainty regarding the safety of leucine consumption. In order to demonstrate that leucine does not cause obesity, we set out to test the hypothesis that high fat diets cause decreased breakdown of BCAA. In the first study, we tested whether one month of BCAA supplementation could increase muscle growth in neonatal pigs. Neither normal pigs nor low birth weight pigs, which have naturally impaired muscle growth, grew better in response to BCAA supplementation, despite low birth weight pigs expressing less of a leucine sensing protein in skeletal muscle. Furthermore, BCAA supplementation caused higher BCAA concentrations in blood plasma, but did not cause pigs to gain more fat, or cause any changes in liver fat metabolism. Having produced strong evidence that BCAA supplementation neither improves lean growth nor causes abnormal fat metabolism, we then tested whether fat supplementation changes BCAA metabolism. Pigs were fed milk replacer formula which was either low calorie (Control), or high calorie from animal fat, which is rich in long-chain fatty acids (LCFA) or high calorie from coconut oil, which is rich in medium-chain fatty acids (MCFA). Although high fat diets did not increase blood plasma BCAA concentrations, the MCFA formula in particular caused changes which could lead to fatty liver disease and decreased breakdown of BCAA. Genes which synthesize new fatty acids were increased in the livers of pigs fed MCFA formula compared to those fed LCFA and Control formulas. Furthermore, liver samples taken from pigs fed the MCFA and LCFA formulas were less able to fully break down metabolites of leucine compared to pigs fed the Control formula. In addition, liver samples from MCFA fed pigs were less able to fully break down metabolites of the BCAA valine, which led to higher concentrations of that metabolite in the blood plasma of pigs fed MCFA formula compared to pigs fed LCFA or Control formula. In the future, it would be valuable to feed a high MCFA formula for a longer period of time to determine whether nonalcoholic fatty liver disease will develop, and whether blood plasma BCAA concentrations will increase due to decreased breakdown. Overall, these studies concluded that long term BCAA supplementation does not increase muscle growth in neonatal pigs, but there is also no indication that they cause obesity or dysfunctional fat metabolism. On the other hand, high fat diets cause impairments in BCAA breakdown which may lead to elevated BCAA concentrations in blood plasma.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/111064 |
| Date | 29 June 2022 |
| Creators | Yonke, Joseph Allan |
| Contributors | Animal and Poultry Sciences, El-Kadi, Samer Wassim, Gerrard, David E., Rhoads, Robert P., Hanigan, Mark D. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | Creative Commons Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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