Against the stream: relevance of gluconeogenesis from fatty acids for natives of the arctic regions.

Background: The question whether even-chain fatty acids can be converted into glucose has a long-standing tradition in biochemistry. Since the glyoxylate shunt is absent from mammals, the question has been considered to be solved. It is of particular relevance for understanding the metabolic state of natives of the arctic regions due to the very high fat content of their traditional diet only containing negligible amounts of carbohydrates.

Methods & Results: Using an in silico approach, we discovered several hitherto unknown routes in human metabolism that allow the conversion of even-chain fatty acids into carbohydrates in humans. These pathways proceed via ketogenesis over the intermediate of acetone and produce the gluconeogenic precursor pyruvate. While these pathways can make a contribution to glucose production during times of limited carbohydrate supply, we found that their capacity might be limited due to a high demand in reducing equivalents in acetone degradation. Considering the traditional diet of natives of the arctic regions, the detected pathways are not only important in order to improve carbohydrate supply, but moreover reduce the amount of protein that needs to be used for gluconeogenesis.

Conclusion: In summary, our study sheds new light on our understanding of the metabolic state of natives from the arctic regions on their traditional diet. Moreover, they provide an avenue for new analyses that can reveal how humans have adapted metabolically to a practically carbohydrate-free diet.