Kaleta, C., de Figueiredo, L. F., Werner, S., Guthke, R., Ristow, M., & Schuster, S. (2011). In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans PLoS Computational Biology, 7 (7) DOI: 10.1371/journal.pcbi.1002116
| Computational studies suggest that human metabolism can produce glucose from fatty acids. This may explain why the Atkins diet isn't quickly lethal, and why the Inuit aren't inherently obese. |
If true, it's also puzzling why certain low-carbohydrate diets (e.g. the infamous "Atkins diet") don't cause more health problems than those for which they're already known. Christoph Kaleta (Friedrich Schiller University of Jena, Germany) and coworkers may have answered such mysteries.
Their computational studies, based on experimental results, suggest that human metabolism may be able to synthesize glucose from fatty acids, albeit at low efficiency.
Identifying metabolic pathways.
The scientists modeled human metabolism on a genome scale, with 3188 metabolites and 5733 reactions. Their model is based on elementary flux patterns, a method of elucidating all biochemical reactions that consume one metabolite and produce another.
They used this approach to determine the shortest biochemical pathways leading from the molecule acetyl CoA (a product of fat metabolism) to glucose 6-phosphate (i.e. gluconeogenesis, glucose production from non-carbohydrate precursors). They also determined the Gibbs free energy of their pathways at 37°C and pH 7.2 (physiologically-relevant conditions).
The Gibbs free energy reports on the overall energetics of the pathways (i.e. how likely they are to proceed). The used measured Gibbs free energy of formation values when known, and estimated otherwise.
Metabolic pathway characteristics.
The scientists identified numerous feasible biochemical pathways from acetyl CoA to glucose 6-phosphate. Three intermediate reactions are essential: cytosolic gluconeogenesis from phosphoenolpyruvate, mitochondrial oxaloacetate from pyruvate carboxylation, and cytosolic acetol from mitochondrial acetoacetate.
They deduced that alternative pathways based on these routes function to either convert (1) acetyl CoA to acetoacetate in the mitochondrion, (2) cytosolic acetol to mitochondrial pyruvate, or (3) mitochondrial oxaloacetate to cytosolic phosphoenolpyruvate. They found nine possible pathways for the first route, and 58 for the second.
Regarding these 58 pathways, 14 of them involve D-lactaldehyde. Many others involve either the reduction of nicotine adenine dinucleotide or the oxidation of nicotine adenine dinucleotide phosphate.
Energetic cost.
All of these pathways are overall energetically favorable. However, some of them require molecular inputs that may slow down other metabolic pathways.
The efficiency of the most energetically-efficient gluconeogenesis pathway from fatty acids is 73%, and that of the least is 53%. This is much less efficient than gluconeogenesis from a typical protein (87%) or glycerol (95%).
These energetic cost results may explain why the Atkins diet helps some people lose weight (and why the Inuit aren't obese). Much energy is required to convert fat to glucose, limiting the health problems that are commonly associated with high-fat diets.
Final comments.
This study doesn't experimentally prove that fatty acids are used in human metabolism to produce sugars, but it does strongly hint at this possibility. These metabolic pathways are highly inefficient, but seem feasible when no other dietary input is available.
NOTE: The scientists' research was funded by the German Ministry for Research and Education, the Foundation for Science and Technology (Portugal), Siemens SA Portugal, as well as the German Research Foundation.
Kaleta, C., de Figueiredo, L. F., Werner, S., Guthke, R., Ristow, M., & Schuster, S. (2011). In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans PLoS Computational Biology, 7 (7) DOI: 10.1371/journal.pcbi.1002116