Science2 publishers2 min readPublished
Bullfrog brains make their own ketone fuel when glucose runs out
University of Missouri researchers report that bullfrog brains make ketone bodies in their own tissue when glucose runs low, a job textbooks give the liver. Any use against stroke or Alzheimer's in people rests, for now, on the argument that frogs and humans share core metabolic pathways.
The Scientist · Science desk
What happened
- The findings appear in PNAS in a paper by Hafsa Yaseen and colleagues describing frog neural activity that keeps running without glucose metabolism on ketones made in the brain.
- Bullfrogs overwinter submerged under frozen ponds, and by late winter their oxygen and glucose are nearly spent just as brainstem circuits must restart breathing.
- Earlier work from Santin's lab found that the frogs' hibernation-like state protects neural circuits during extreme oxygen deprivation.
- The researchers do not think the switch to brain ketone production is permanent, and what triggers it and how long it can last are still open questions.
Compiled by The ScientistSomething wrong?How this is made
Why it matters
- contradiction One account says the frog brain skips liver delivery altogether and the other says it stops relying entirely on the liver, so whether local ketones replace or supplement the liver's supply is unsettled.
- capability A vertebrate brain that keeps circuits active on ketones it makes itself gives researchers a working system for finding what switches local synthesis on.
- constraint Stroke and Alzheimer's applications depend on first finding the same local pathway in mammalian brain tissue, a step this frog study does not take.
A local source matters because neurons short of fuel fail quickly. When glucose runs low or blood flow fails, neural firing falters. Neuroscience News, working from the university's release, says the cascade that follows can cause permanent neuronal death within minutes [4]. In the textbook fallback, the liver breaks down fatty acids and releases acetoacetate and beta-hydroxybutyrate into the blood, and those molecules must then cross the blood-brain barrier before a neuron can use them [3].
"Scientists generally believe ketones are delivered to the brain from elsewhere in the body," said Joseph Santin, an associate professor of biological sciences at Mizzou whom the university describes as the study's lead author [5][7]. "It's like finding a backup generator inside a building that everyone assumed had only one power source," he said [6]. The animals were North American bullfrogs, Lithobates catesbeianus [8].
The two write-ups are not equally confident about spring recovery. Neuroscience News states that local ketogenesis provides the on-site fuel needed to keep brainstem circuits running without waiting for slower organs to recover [10]. Phys.org says only that the backup "may be one reason" the frogs make that transition quickly and successfully [11].
The thing this doesn't tell you is whether frogs need the pathway to wake up. Showing that brain tissue can make a fuel is one result. Showing that the animal fails without it would mean blocking the pathway and watching recovery falter. Neither account describes the experimental preparation, reports how much ketone the tissue produced, or says whether such a block was tried.
For people, the argument rests on shared machinery. I think the study is solid news about frog physiology and a hypothesis about human brains. Santin believes the work may help explain the human brain because bullfrogs and humans share many fundamental biological processes, and phys.org lists Alzheimer's disease, ALS and schizophrenia as energy-linked disorders the research could open up for study [16]. Neuroscience News adds stroke to its list of glucose-starved conditions [17].
What to watch
- A test in which blocking ketone synthesis in the frog brain impairs recovery of breathing circuits after overwintering.
- Evidence that mammalian brain tissue can produce ketone bodies locally under glucose deprivation.
- Identification of the signal that switches frog brain tissue over to ketone production.