More than one way to fuel a brain

Metabolism in mammals is more flexible than previously thought

© Katrin Boes / MPI-CBG

Our bodies are fueled by glucose, but when glucose runs low our cells can switch to alternative energy sources, such as fatty acids. The brain, however, cannot directly use fatty acids for energy production. Instead, fatty acids can be converted into so-called “ketone bodies”, which the brain uses during fasting or when glucose is scarce. Also, the developing human brain has high energy requirements and relies on ketone bodies as a major fuel. Therefore, it was suggested in former studies that ketone body production has been an important metabolic process for brain size expansion during human evolution.

In a recent study, published in the journal eLife, Michael Hiller, research group leader at the CSBD, the Max Planck Institute of Molecular Cell Biology and Genetics, and the Max Planck Institute for the Physics of Complex Systems, found together with David Jebb, a postdoc in the group investigated the key enzyme required for ketone body production, HMGCS2. Surprisingly, they found that three different groups of mammals, old world fruit bats, whales and dolphins, and elephants have lost HMGCS2 during evolution. In fruit bats, the loss of this enzyme and thus ketone body production may explain their high sensitivity to starvation. Indeed, these bats often die after starving for more than 24 hours. In contrast to these bats, dolphins and whales, as well as elephants can withstand longer periods of fasting. This shows that alternative strategies to fuel the brain under starvation evolved repeatedly in mammals.

David Jebb, the first author of the study explains: “An even more unexpected result is that dolphins and elephants, which are thought to be highly intelligent and have exceptionally large brains for their body size, have lost this enzyme. This raised an interesting question of whether ketone body production was lost before or after brain size expansion during evolution.” The scientists could show that the HMGCS2 gene was lost before brain expansion in dolphins and modern elephants. Michael Hiller concludes: “This shows that, in contrast to human, production was not essential for brain expansion in other mammals. Our findings also demonstrate that text-book knowledge from humans and mice cannot always be extrapolated to other mammals.”


Original Publication
David Jebb, Michael Hiller: Recurrent loss of HMGCS2 shows that ketogenesis is not essential for the evolution of large mammalian brains.
eLife, 16 October 2018