Hormone alerts brain to fat-storage status, but its packaging system goes awry in obesity.

Calorie restriction does, on the whole, lead to weight loss. But nutrition and energy researchers might rephrase that axiom to more accurately read: “Calories in (a bunch of stuff happens in the body and the brain that influences) calories out.”

A new study published in the journal Developmental Cell uncovers several steps of that complex internal communication system — in fruit flies.

Yes, fruit flies have fat too. Just not very much.

There’s reason to believe these newly discovered molecular pieces of the obesity puzzle could be important in humans, said Dr. Akhila Rajan, a basic scientist at Fred Hutchinson Cancer Research Center and lead author of the study.

In a previous study conducted at Harvard Medical School, where she completed her postdoctoral fellowship, Rajan and colleagues found that a hormone — leptin — which travels from fat to brain exists in both humans and fruit flies. In fact, the human version of leptin can sub in for the insect version of the hormone in genetically engineered flies.

In obese people, something goes awry with leptin, which acts as a readout of the body’s fat-storage levels. The hormone’s packaging system changes, but it’s not clear exactly where that dysfunction arises. If those details were worked out, it’s possible that fixing leptin’s packaging could be a new therapeutic avenue to battle obesity, Rajan said.

The other pieces of the signaling chain that the researchers identified in their latest study are also largely the same in fruit flies and people. These new pieces include a protein that shuttles the fly leptin across the border of fat cells. Rajan, Harvard developmental biologist Dr. Norbert Perrimon and their colleagues also found that high levels of calcium, triggered during starvation, block leptin’s migration.

Fat, it turns out, is not just a passive energy storage compartment, but an active participant in brain function. Our fat can signal our body’s overall nutritional status — sated or starved — through a complex and not completely understood trafficking system of hormones, proteins and other molecules that travel from our love handles to our brains and back again.

The key player in that traffic pattern is leptin. You might think of this hormone as the supervisor of the body’s storage facility, alerting management whether the energy stores are replete or empty. The brain acts very differently in periods of plenty or starvation — during starvation, when leptin levels are low, appetite increases and energy expenditure lowers.

So when leptin is down, that means the “calories out” part of the equation is down too, since you’re expending less energy and your brain might be more inclined to increase the “calories in” cue to eat.

The hormone is made inside fat cells, and it is then released from cells and ferried through the blood to the brain. Who the hormone’s molecular ferry pilots are, though, is not known.

Previous research in humans has found that leptin levels in the blood increase in obese people, but the form of the hormone also changes, Rajan said. In obese people, leptin seems to have different ferrying partners - or is even left alone without a driver in the circulation - meaning it can’t cross the blood-brain barrier.

It’s thus possible - although not yet proven - that the hormone can’t get its fat tally to its final destination in obese people, meaning their brains literally might not be able to recognize their own fat. And maybe, once researchers understand more about leptin’s packaging system and which pieces are missing in obesity, they could give back the missing proteins in the form of a therapeutic that would allow leptin to traffic to the brain normally.

“If you know that the packaging material is missing, you could provide more of the packaging mat