Role of dietary derived propionyl-CoA in the prevention of obesity-induced health impairments
Final Report Abstract
Recent data provide evidence for an improvement of diet-induced hepatic steatosis and insulin resistance by propionate which is intestinally produced from fermentable fiber. Correspondingly, odd-chain fatty acids (OCFA) in plasma phospholipids are induced, indicating that propionyl-CoA (Pr-CoA) is used for fatty acid synthesis. Beside their consideration as biomarkers for dairy intake, OCFA are related to an improved insulin sensitivity and type 2 diabetes risk. However, causal relationships are not elucidated. The overall aim of this project was to determine the impact of two main fractions of dairy, milk fat and milk protein on OCFA levels and their influence on health outcomes under high-fat diet (HFD) conditions. Both fractions represent viable sources of OCFA, as milk fats contain a significant amount of OCFA and milk proteins are high in branched chain amino acids (BCAA), namely valine (Val) and isoleucine (Ile), which can produce Pr-CoA, a precursor for endogenous OCFA synthesis, while leucine (Leu) does not. Additionally, this project sought to clarify the specific metabolic effects of the OCFA heptadecanoic acid (C17:0). Various shortterm and long-term feeding studies were performed using male C57BL/6JRj mice fed HFD diets supplemented with milk fat or C17:0, as well as milk protein or individual BCAA (Val; Leu) to determine their influences on OCFA and metabolic health. Short-term feeding revealed that both milk fractions induce OCFA in vivo, and the increases elicited by milk protein could be, in part, explained by Val intake. In vitro studies using primary hepatocytes further showed an induction of OCFA after Val treatment via de novo lipogenesis and increased α-oxidation. In the long-term studies, both milk fat and milk protein increased hepatic and circulating OCFA levels; however, only milk protein elicited protective effects on adiposity and hepatic fat accumulation—likely mediated by the anti-obesogenic effects of an increased Leu intake. In contrast, Val feeding did not increase OCFA levels nor improve obesity, but rather resulted in glucotoxicity-induced insulin resistance in skeletal muscle mediated by its metabolite 3-hydroxyisobutyrate (3-HIB). Finally, while OCFA levels correlated with improved health outcomes, C17:0 produced negligible effects in preventing high-fat diet induced health impairments. The results presented herein demonstrate that the beneficial health outcomes associated with dairy intake are likely mediated through the effects of milk protein, while OCFA levels are likely a mere association and do not play a significant causal role in metabolic health under high-fat conditions. Furthermore, the highly divergent metabolic effects of the two BCAA, Leu and Val, unraveled herein highlight the importance of protein quality.
Publications
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“Role of Branched-Chain Amino Acids in Hepatic Lipid Metabolism”; Metabolism in Action - Central and peripheral control of energy metabolism; October 2019, Hillerød, Denmark
Bishop, C. A., Weitkunat, K. & Klaus, S.
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“Role of dietary derived propionyl-CoA and odd-chain fatty acids in hepatic lipid metabolism”; NuGOweek 2019, 16th edition, From foodomics to nutrigenomics – Translating food composition data into healthy diets; September 2019, Agroscope, Bern, Switzerland
Weitkunat, K., Bishop, C. A., Uhlemann, M. & Klaus, S.
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The branched‐chain amino acids valine and leucine have differential effects on hepatic lipid metabolism. The FASEB Journal, 34(7), 9727-9739.
Bishop, Christopher A.; Schulze, Matthias B.; Klaus, Susanne & Weitkunat, Karolin
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“High-fat valine feeding drives adiposity & glucose intolerance”; Metabolism Month – An online conference about energy control and metabolism; March 2021
Bishop, C. A., Henning, T., Machate, T., Klaus, S. & Weitkunat, K.
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Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle. Nutrition & Diabetes, 12(1).
Bishop, Christopher A.; Machate, Tina; Henning, Thorsten; Henkel, Janin; Püschel, Gerhard; Weber, Daniela; Grune, Tilman; Klaus, Susanne & Weitkunat, Karolin
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Influence of dairy intake on odd-chain fatty acids and energy metabolism. Doctoral dissertation, University of Potsdam
Bishop, C. A.
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“Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine”; 59. Wissenschaftlicher Kongress der Deutschen Gesellschaft für Ernährung e. V.; Proc. Germ. Nutr. Soc., Vol. 28 (2022) 35
Bishop, C. A., Machate, T., Henning, T., Henkel, J., Püschel, G., Grune, T., Klaus, S. & Piepelow, K.
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Heptadecanoic Acid Is Not a Key Mediator in the Prevention of Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice. Nutrients, 15(9), 2052.
Bishop, Christopher A.; Machate, Tina; Henkel, Janin; Schulze, Matthias B.; Klaus, Susanne & Piepelow, Karolin
