Thursday, 27 August 2015

SCFAs and ketones - similar molecules with similar effects

Short-chain fatty acids (SCFAs) and ketones are produced in the body by two opposing extremes of nutrition. Under the fed state, SCFAs are produced by bacterial fermentation of carbohydrate (starch and fibre) in the colon; whereas under the fasting state, ketones are produced by the liver from fat (β-oxidation) to provide alternate fuel to glucose. SCFAs and ketones are major mediators of the health benefits of high and low carb diets respectively. Moreover they are actually very similar molecules, with very similar effects on the body!

The main SCFAs: acetate (C2H4O2), propionate (C3H6O2) and butyrate (C4H8O2)
The ketone bodies: β-hydroxybutyrate (C4H8O3), acetoacetate (C4H6O3) and acetone (C3H6O)

Energy - SCFAs and ketones can be used for energy, where they essentially undergo the same metabolism: conversion to acetyl-CoA and oxidation in Krebs cycle. When consuming carbohydrate/fibre, the gut microbiota-derived SCFAs apparently supply the body with about 5-10% daily energy, whereas during fasting, ketones can meet about 70% of the brains energy requirements (glucose is still required).

Epigenetics - SCFAs and ketones modulate acetylation-based epigenetics: firstly by increasing acetyl-CoA and therefore priming acetylation (histone acetyltransferases); secondly by inhibiting histone deacetylases. All major SCFAs possess histone deacetylase inhibitor (HDI) activity, which mediates many of their beneficial effects including anti-inflammatory activity, anti-cancer effects and stress resistance 1–3. Similarly HDI activity is emerging as a major mediator of the benefits of the main ketone β-hydroxybutyrate (BHB) 4; note BHB only differs from butyrate by one hydroxyl group. Of all SCFAs and ketones, butyrate is the most potent HDI, with relative potency being: butyrate > propionate > acetate and butyrate > BHB > acetoacetate. However potency in vivo obviously depends on physiological concentrations in specific tissues. For instance SCFAs reach their highest concentrations in the gut-immune tissue.

Receptors - SCFAs and ketones are also ligands for some G protein-coupled receptors (GPRs); here the slightly different molecular structures come into effect. SCFAs have been found to bind and activate several GPRs (e.g. GPR41, GPR43 and GPR109) 1,3. Less research has been done on ketones. However both butyrate (SCFA) and BHB (ketone) are able to activate GPR109 1. Also propionate (SCFA) and BHB (ketone) have been found to oppositely regulate GPR41 to increase and decrease sympathetic nervous system activity respectively 5. These different signaling outcomes may be important for adapting body metabolism to opposing feeding states 5. Under the fed state, SCFA-GPR41 signaling may increase sympathetic tone, metabolic rate, leptin and PYY/GLP-1 (increase insulin sensitivity and satiety) 1. Whereas under the carb fasting state, ketone signaling lowers sympathetic tone and metabolic rate 4.

References
1.         Kasubuchi, M., Hasegawa, S., Hiramatsu, T., Ichimura, A. & Kimura, I. Dietary Gut Microbial Metabolites, Short-chain Fatty Acids, and Host Metabolic Regulation. Nutrients 7, 2839–2849 (2015).
2.         Canani, R. B. et al. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J. Gastroenterol. 17, 1519–28 (2011).
3.         Kim, C. H., Park, J. & Kim, M. Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. Immune Netw. 14, 277–88 (2014).
4.         Newman, J. C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).
5.         Kimura, I. et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108, 8030–5 (2011).

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