When the human body needs extra energy, the brain tells fat cells to release their stores. Now, for the first time, researchers have visualized the nerves that carry those messages from brain to fat tissue. The activation of these nerves in mice, they found, helps the rodents lose weight—an observation that could lead to new slimming treatments for obese people.
“The methods used here are really novel and exciting,” says neuroendocrinologist Heike Muenzberg-Gruening of Louisiana State University’s Pennington Biomedical Research Center in Baton Rouge, who was not involved in the new study. “Their work has implications for obesity research and also for studying these nerves in other tissues.”
Diagrams of the chatter between the brain and fat tissues have long included two-way arrows: Fat cells produce the hormone leptin, which travels to the brain to lower appetite and boost metabolism. In turn, the brain sends signals to the fat cells when it’s time to break down their deposits of fatty molecules, such as lipids, into energy. Researchers hypothesized that there must be a set of nerve cells that hook up to traditional fat tissue to carry these messages, but they’d never been able to indisputably see or characterize them.
Now they have. Thanks to two forms of microscopy, neurobiologist Ana Domingos, of the Instituto Gulbenkian de Ciência in Oeiras, Portugal, produced images showing bundles of nerves clearly enveloping fat cells in mice. She and her colleagues went on to show, using various stains, that the nerves were a type belonging to the sympathetic nervous system that stretches outward from the spinal cord and keeps the body’s systems in balance.
“People had looked at thin slices of fat tissue before, and it was really hard to tell what you were looking at,” Domingos says. Her team, on the other hand, used techniques that let them image a whole tissue at once. “The images we created really established that there are nerves terminating in the fat tissue.”
Then, to probe those nerve cells’ roles in obesity, the researchers genetically engineered mice so that they could selectively turn on the sympathetic nerves within rodent fat tissues using a laser; it was the first time researchers had used so-called optogenetics to control cells in the sympathetic nervous system rather than in the brain and spinal cord that make up the central nervous system. Turning on those nerves, Domingos and colleagues report today in Cell, mimicked the effect that increasing leptin does, stimulating fat breakdown. Alternatively, when they engineered mice to lack the sympathetic nerves, increasing leptin levels no longer led to a breakdown of fat cells.
“If we can find drugs that specifically activate those neurons in people, we might be able to have an effect on obesity,” Domingos says. Many obese individuals, she points out, are resistant to leptin—their brain stops responding to high levels. Turning on the nerves that the brain uses to send signals in response to leptin, her findings suggest, could be a way around this resistance.
This year, the Food and Drug Administration approved the first nerve blocker to treat obesity by interrupting messages between the stomach and the brain, but how it works at a cellular level is poorly understood. “There’s a lot of concern that with something like that, we’re blocking both good and bad nerve fibers,” says Muenzberg-Gruening, who suggests that specifically targeting the newly discovered nerves in fat may lead to fewer side effects. But questions remain, she adds, about whether other types of nerves are also signaling fat cells, and whether the fat cells receiving signals are themselves unique.