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

If you’re one of the millions of Americans who’s ever tried to lose weight, you’ve probably heard the old dieting chestnut, “calories in, calories out.”

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 Monday 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’s storage and packaging systems

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 material to the obese cell, with the hope of making the quality of leptin [that] can access the brain,” Rajan said.

There are a lot of unknowns to solve first, though. Those findings about leptin in obese people led Rajan to first ask, “Is the problem starting right in the fat cell?”

To answer that question, she and her colleagues turned to the tiny fruit fly.

‘Something which affects us every day’

Fruit flies might seem an unlikely model to study human obesity. They’re small, weighing on average about a quarter of a milligram — it would take nearly 250 million of them to equal the weight of a single, non-obese human. And even if you overfeed them, flies don’t really get fat. For one, they have an exoskeleton that acts like a girdle, keeping them more or less the same size.

But they can develop metabolic disorders that mimic those in humans, like diabetes, Rajan said. And they’re much easier to study than humans, or even mice.

The fruit fly version of leptin is known as Unpaired 2, or Upd2. To answer the question of how Upd2 gets from inside fat cells, where it is made, to outside the cells, the researchers eliminated, one at a time, the molecules known to be involved in cell secretion in fruit flies. They found that when a secretion protein called GRASP is eliminated, Upd2 gets stuck inside the fat cells. They also saw that flies missing GRASP had metabolic dysfunctions similar to those observed in flies missing Upd2.

Multiple copies of GRASP stick together to cluster around Upd2, forming a special portal between the inside and outside of the fat cell.

“I almost think of it like a ramp which allows [Upd2] to get on the highway, to go outside,” Rajan said.

When the researchers starved the flies, the ramp stopped working. The GRASP protein was inactivated in such a way that it no longer stuck to itself. The protein clusters dissolved, they saw, and Upd2 couldn’t get out.

This process depends on calcium, which builds up in cells under starvation. The rising tide of calcium, in turn, is spurred by a “starvation hormone,” glucagon.

Most exciting to Rajan, the trafficking molecules they’ve identified in this study all exist in humans. Next up, she wants to study human fat cells to see if these conserved proteins are acting the same way to traffic our leptin.

Rajan and members of her recently established lab at the Hutch are also working to understand what happens to leptin once it leaves fat cells. How does it get from the surface of fat cells to the brain? They’re now looking for the proteins that partner with leptin in the next phase of its journey.

That’s a lot of detailed steps still to work out in the pathway from nutrition to fat storage to the brain. In the end, Rajan is motivated to solve the complicated system’s mysteries because it’s “something which affects you and me every day,” she said.

The National Institutes of Health and the Howard Hughes Medical Institute funded this research.

Rachel Tompa, a staff writer at Fred Hutchinson Cancer Research Center, joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at rtompa@fredhutch.org or follow her on Twitter @Rachel_Tompa. 

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