Whether you are fat or thin isn’t directly determined by your eating habits, suggest researchers who report new findings made in worms in the June issue of Cell Metabolism, a publication of Cell Press. While both feeding and fat in worms depends on serotonin levels in the nervous system, they found evidence that the nerve messenger acts through independent channels to control whether you eat versus what to do with those calories once you've eaten them.
"It says that the nervous system is a key regulator coordinating all energy-related processes through distinct molecular pathways," said Kaveh Ashrafi of the University of California, San Francisco. "The nervous system makes a decision about its state leading to effects on behavior, reproduction, growth and metabolism. These outputs are related, but they are not consequences of each other. It's not that feeding isn't important, but the neural control of fat is distinct from feeding."
If the results in worms can be extrapolated to humans, as Ashrafi suspects at a fundamental level they can given serotonin’s ancient evolutionary origins, then the finding may have clinical implications.
"From a clinical perspective, this may mean you could develop therapeutic strategies to manipulate fat metabolism independently of what you eat," he said. "Now, the focus is primarily on feeding behavior. As important as that is, it's only part of the story. If the logic of the system is conserved across species, a strategy that focuses solely on behavior can only go so far. It may be one reason diets fail."
While fat regulation is at one level a relatively simple balance between energy intake and expenditure, the physiology is nonetheless quite complex, Ashrafi said. It was the researchers goal in the new study to dissect that complexity using the worm C. elegans, an organism that is much simpler to work with in comparison to mammals.
They found in the worms that control of feeding by serotonin involves receptors whose function is not required for fat control. Rather, the nerve messenger's effects on fat depend on a separate neural channel and receptor that spark signals leading to the breakdown of fat. The byproducts of that process generated in fat then come “full circle” and control feeding behavior, Ashrafi said.
The findings show that, as in mammals, C. elegans feeding behavior depends on cues in the environment as well as internal cues. Moreover, the researchers said, "obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability."
In both the worm C. elegans and in mammals, high serotonin levels are already known to lead to fat loss while low serotonin levels lead to fat accumulation, the researchers noted. However, there are some differences. In C. elegans, when serotonin goes up, feeding goes up and fat goes down. On the other hand, high serotonin leads people to eat less and shed fat.
Since C. elegans directly match their feeding rates to increasing and decreasing food concentrations, serotonin's effects on fat and feeding in the worms are consistent with the nerve messenger's role as a sensory gauge of nutrient availability, the researchers said. When resources are scarce, worms build up their fat reserves. Thus, the perception of food scarcity leads them to shift to a metabolic state favoring conservation of energy and the direction of nutrients to fat stores.
Despite those differences, Ashrafi said, given the contributions of the serotonin pathway to energy balance across species, "we speculate that human counterparts of feeding-independent fat regulatory genes identified in our study may similarly regulate energy balance."
The researchers include Supriya Srinivasan, University of California, San Francisco, San Francisco, CA; Leila Sadegh, University of California, San Francisco, San Francisco, CA; Ida C. Elle, University of Southern Denmark, Odense M, Denmark; Anne G.L. Christensen, University of Southern Denmark, Odense M, Denmark; Nils J. Faergeman, University of Southern Denmark, Odense M, Denmark; and Kaveh Ashrafi, University of California, San Francisco, San Francisco, CA.