Inuit metabolism revisited: what drove the selective sweep of CPT1a L479?

Abstract

This article reassesses historical studies of Inuit metabolism in light of recent developments in evolutionary genetics. It discusses the possible selective advantage of a variant of CPT1a, which encodes the rate limiting enzyme in hepatic fatty acid oxidation. The L479 variant of CPT1a underwent one of the strongest known selective sweeps in human history and is specific to Inuit and Yu'pik populations. Recent hypotheses predict that this variant may have been selected in response to possible detrimental effects of chronic ketosis in communities with very low carbohydrate consumption. Assessing these hypotheses alongside several alternative explanations of the selective sweep, this article challenges the notion that the selection of L479 is linked to predicted detrimental effects of ketosis. Bringing together for the first time data from biochemical, metabolic, and physiological studies inside and outside the Inuit sphere, it aims to provide a broader interpretative framework and a more comprehensive way to understand the selective sweep. It suggests that L479 may have provided a selective advantage in glucose conservation as part of a metabolic adaptation to very low carbohydrate and high protein consumption, but not necessarily a ketogenic state, in an extremely cold environment. A high intake of n-3 fatty acids may be linked to selection through the mitigation of a detrimental effect of the mutation that arises in the fasted state. The implications of these conclusions for our broader understanding of very low carbohydrate metabolism, and for dietary recommendations for Inuit and non-Inuit populations, are discussed.