Product of Metabolism Also Goes Awry in Neurodegenerative Disease
Researchers at UC San Francisco have identified the chemical that signals to roundworms when they are hungry and should eat, and when they are sated and can stop. Because this chemical, kynurenic acid, has also been implicated in many human diseases, including neurodegenerative conditions such as Alzheimer’s disease and Huntington’s disease, the finding may provide useful clues for understanding and treating these disorders.
The scientists, working in the UCSF laboratory of Kaveh Ashrafi, PhD, measured neurotransmitter and gene activity in the neural circuit that governs eating behavior in the microscopic worm C. elegans. The team charted changes as the worms ate, were deprived of food, and then were allowed to eat again after a period of fasting.
As reported in the January 15, 2015 issue of Cell, the researchers found that when worms were given access to food after they’d been denied it, they would overeat for a while before resuming their typical feeding pattern, a change in behavior triggered by falling levels of kynurenic acid.
Though the research focused on the mechanics of feeding behavior, the finding sheds light more broadly on the molecular processes underlying “behavioral plasticity,” the ability to initiate different kinds of behavior in different circumstances, said Ashrafi, senior author of the new study and associate professor of physiology at UCSF.
“The specific question we were asking in these experiments was, ‘How does an organism know it’s hungry and, as it eats, how does it know it’s eaten?’” Ashrafi said. “But we want to understand at a basic molecular level how an animal incorporates experience and uses it to regulate behavior.”
Ashrafi’s team measured the worms’ eating behavior with several methods, including experiments in which they added fluorescent dyes to the E. coli bacteria the worms feed on to track how quickly the worms ingested them. After establishing a baseline eating rate, the researchers withheld food from the worms for one, two or four hours, then provided food again and measured the changes in the worms’ eating rate. Fasting for more than one hour caused the worms to enter a “hyperactive feeding state” of more rapid eating, which lasted for about one hour.
Previous research in the Ashrafi lab had shown that hyperactive feeding in C. elegans occurs when levels of the neurotransmitter serotonin increase. Both serotonin and kynurenic acid are metabolites of tryptophan, an essential amino acid that C. elegans as well as humans need but cannot synthesize—it must be derived from food.
To explore the relationship between feeding and serotonin levels more deeply, the research team designed a series of experiments that measured metabolic changes in worms during fasting and feeding states and modified the activity of certain genes that they suspected were important in controlling different levels of feeding.
They discovered that when the worms fast, levels of kynurenic acid are depleted, which sets off a cascade of events in which a set of neurons that are normally held in check are activated. These neurons then increase their secretion of a substance called neuropeptide Y, which in turn leads another set of neurons to pump out greater amounts of serotonin.
“Normally, kynurenic acid acts like a brake,” Ashrafi said. “When an animal is fasting, it removes the brake and certain neurons become active. The changes in this metabolite explain the period of overeating and the resumption of normal eating.”
The study reveals that the kynurenic pathway is a key neurochemical player deserving of further attention, said Ashrafi. “We know metabolism can have many effects on brain function, and this work explains something general about the nervous system that applies to neural functions beyond feeding. Metabolism affects the actions and responses of neurons in fundamental ways, and similar processes are likely to be going on in the human brain.”
Other UCSF researchers participating in the research were George A. Lemieux, PhD, associate research specialist; former postdoctoral fellow Katherine A. Cunningham, PhD; Lin Lin, junior research specialist; Fahima Mayer, research associate; and Zena Werb, PhD, professor and vice chair of anatomy.
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