Normal 0 false false false MicrosoftInternetExplorer4 Worms have it all backward. According to the diet books, it’s supposed to be eat more, weigh less. But when roundworms fall on tough times, they bulk up while eating less.
Now researchers at the University of California, San Francisco have genetically dissected the brain circuits responsible for that paradox. Call it denial. Call it what you will. The study, published in the Aug. 6 Cell Metabolism, shows that the brain of the nematode Caenorhabditis elegans considers eating and making fat separate activities.
Dieters know all too well that cutting calories doesn’t always lead to weight loss. The new work, led by geneticist Kaveh Ashrafi, may help unravel that mystery and one day lead to treatments for obesity. The new findings also may help explain some of the variation in body weight seen among humans.
Many of the roundworm pathways identified in the new UCSF study are present in mammals, including humans, and may work in similar ways, but the details are likely to vary, say Leon Avery and Young-jai You, behavioral geneticists at the University of Texas Southwestern Medical Center at Dallas. The new study shows “how the soldiers carry out orders,” Avery says, and points researchers toward molecules likely to play a role in human metabolism.
Collaborating with researchers from the FredHutchinsonCancerResearchCenter and University of Washington in Seattle, the UCSF team showed that a peptide called DAF-7 is made in a sensory neuron in the worm’s head when there is plenty of food and not too many other worms in the neighborhood. DAF-7 is a member of the TGF-beta family of signaling molecules, which are involved in regulating fat metabolism in mammals.
“A worm is a machine that is beautifully designed to take food and convert it to lots of worms,” Ashrafi says. But when food is scarce or conditions are crowded, worms slow down their feeding rate, build fat stores and stop making and laying eggs. If things get really bad, the worms enter a type of hibernation known as a dauer form.
Ashrafi’s group found that DAF-7 controls all those responses by sending the signal of plenty to just two pairs of interneurons in the worm’s brain. Interneurons link sensory neurons with neurons that control movement. The interneurons are known as RIM and RIC, and they function as a central processing unit for information about the environment.
Those interneurons then divide the tasks of altering reproduction, feeding and metabolism among other neurons. RIM and RIC make peptide hormones similar to adrenaline and noradrenaline. The peptide hormones tell the neurons that control swallowing to speed up or slow down feeding. Using several different mutant worms, the researchers demonstrate that feeding was independent of fat storage. Worms lacking DAF-7 eat 20 percent to 30 percent less than normal worms, but they build up 2.5 times more fat. Restoring feeding to the normal rate did nothing to fat storage.
Fat storage, the researchers found, is controlled by other neurons that get signals through a neurochemical called glutamate. The researchers’ next steps will include tracking down the molecules neurons use to trigger fat production and storage.
In June, Ashrafi and his colleagues published results of a study on the brain chemical serotonin. That study also demonstrated that eating and making fat are coordinated, but separate phenomena.
“These processes are regulated through independent neural pathways. They are coordinated, but they are not consequences of each other,” Ashrafi says. That is not to say that eating too much won’t make you fat, just that different neurons control the processes, so there is independent control over the activities.
“Of course feeding is important to how much energy comes in, but it is up to the nervous system to decide what to do with the nutrients — send it for storage or expend it,” Ashrafi says.
People don’t hibernate, so the fat buildup seen in the worms may not be directly applicable to the way humans regulate fat production, says You of UT Southwestern. Still, she says, “We are very excited about Kaveh’s work.”
