Whenever my nose drags me into a bakery, I could really do with an IV drip of this leptin stuff. Leptin is a hormone that tells your brain you’re full, thus helping to regulate how much you eat. Though I’m not sure any amount would be enough to prize my fingers off a cupcake…
Leptin is also important because it triggers, via the brain, the breakdown of fat when we need an energy boost, but mechanisms behind this important signaling pathway had been hazy. Now scientists think they’ve figured it out, visualizing for the first time the nerve cells that wrap themselves around fat cells in rodents. And when these neurons get excited, via leptin, fat cells get depleted. This finding is important, because some obese people are actually resistant to leptin and thus struggle to lose weight, so ultimately we might be able to use this information to treat them.
First discovered some 20 years ago, leptin is produced by fat cells, or adipocytes, in levels proportional to a person’s body fat mass. It acts as a kind of fat thermostat, helping maintain body fat within a small range. Leptin travels via the blood and acts on the brain. When lots of it is present it signals satiety, reducing hunger but also boosting metabolism, encouraging adipocytes to burn their fatty molecules and generate energy. Conversely, when there isn’t a lot of leptin floating around, appetite is increased and metabolism is dampened.
But there is a missing link in this story: what happens in the middle? Or more specifically, how does leptin stimulate this breakdown of fat? Could there be an unknown population of nerve cells providing some signaling that scientists have been missing? To find out, researchers at the IGC in Portugal in collaboration with Rockefeller University turned to rodents.
As described in Cell, they started off by using highly sensitive microscopy technique to examine fat tissue in mice, which showed that the ends of some unidentified nerve cells were actually enveloping individual adipocytes, creating a junction between the nervous system and fat. Further examination via the use of markers that stick to certain molecules revealed that these belonged to the sympathetic nervous system. Forming part of the peripheral nervous system that transmits information to and from the brain and spinal cord, the sympathetic nervous system helps make localized adjustments to keep the body’s internal state the same.
Next, they used a wonderfully sophisticated technique to selectively activate this specific population of nerves in live mice. Called optogenetics, this involves adding in genes for light-sensitive proteins that can be activated by a laser. When the researchers switched on these neurons, they were able to recreate the events that follow leptin signaling – fatty molecules broke down, and there was a reduction in fat mass. This increase in metabolism was found to be triggered by the release of a chemical called norepinephrine from the neurons.
Tying this together neatly, they found that mice genetically engineered to lack these neurons did not respond to leptin signals, and consequently the hormone was unable to trigger the breakdown of fat. While it’s a bit too early to tell whether this could have implications for obesity treatment in those with leptin resistance, for now it helps fill in gaps of this important pathway.
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