Fruit flies add more weight to theory that individual bodies have set points

The idea that we may have weight set points — a weight that an individual’s body tries to maintain even as food intake and energy expenditure fluctuate — has been floated by obesity researchers to help explain why weight loss can be such a challenge.

“The set point is a concept, but there is no mechanism of how it is regulated,” said Fred Hutchinson Cancer Research Center physiologist Dr. Akhila Rajan.

In a new study published Sept. 24 in the journal Cell Metabolism, Rajan and staff scientist Dr. Ava Brent reveal, using fruit flies, how a hormone released by fat interacts with a neural circuit that regulates insulin release in a way that could establish a body-weight set point. Unexpectedly, the team learned insulin resets its own brake, potentially preventing fluctuations in weight.

“For the first time, this study shows that hormones controlling how two neurons talk to each other, in this particular synapse, to regulate the set point,” Rajan said.

How the body senses its energy stores

Fat is best-known as a form of long-term energy storage. Excess calories, whether they arrive in the form of carbohydrate, protein or fat, can be converted to fat so that the energy within them can be used later. But fat is not a mere inert energy stockpile. It’s the source of important cellular building blocks, like the lipids that keep our cell membranes supple. Fat is also talkative: It’s continuously communicating with our brains and bodies to tell us how much energy is available — not just for a walk around the block, but also for activities that drain our energy without conscious thought, like growing a fetus or fighting off an infection.

Our brains and bodies use a highly complex system of molecular and cellular processes to store, sense and use energy. That’s why Rajan studies the problem in Drosophila fruit flies, which use a similar, but more streamlined, system. In particular, she focuses on the fruit-fly versions of two key hormones: leptin and insulin.

Leptin is the hormone that fat cells send out as an update on the status of their lipid stores.

“If a fly didn't have that signal, it would basically consider itself hungry and just go look for food,” Brent said.

Leptin lets the fly know there’s enough energy stored for it to do things like sleep or reproduce. Many of these activities are regulated by insulin, which also increases as leptin levels rise.

Both leptin and insulin levels change in response to short-term and long-term signals. Both spike after a meal. And body fat is always releasing a trickle of leptin — which gets translated into a trickle of insulin — to reflect how much energy is available for use. It’s this long-term role of leptin that most interests Rajan. 

Leptin-like hormone involved in self-regulating neural circuit

Rajan and Brent wanted to learn more about how leptin signals in the fruit fly brain to cause the increase in insulin that lets the fly know it has enough energy stored to perform specific activities.

In humans, insulin is released by the pancreas. But fruit flies don’t have a pancreas. Instead, the fruit fly version of insulin is released by a cluster of insulin-producing cells in the fly’s brain. Rajan had previously identified the energy store-sensing neurons in the brain that respond to the leptin-like hormone that’s released by fruit-fly fat. It was already known that insulin levels increased as nutrient stores accumulated.

Brent found that that the insulin-producing cells and energy store-sensing neurons were in direct contact with each other.

Neurons can either dampen or help excite the neurons that are downstream of them in a brain circuit. The energy store-sensing neurons are the first type: By touching the insulin-producing cells, they rein in their activity and prevent insulin release. But fly leptin, the signal these dampening neurons respond to, triggers insulin release. How?

Brent discovered that instead of increasing the dampening power of the energy store-sensing neurons, leptin instead reduces it, by releasing the brake they’re applying to the insulin-producing cells. It does this by reducing the number of contacts between the two types of neurons — freeing the insulin-producing cells to release insulin.

When Brent fed the flies a high-fat diet to increase their fat stores and bump up leptin levels, she saw that the number of contacts, or synapses, between the energy store-sensing neurons and the insulin-producing cells dropped. As the restraint on their activity slackened, the insulin-producing cells could release more insulin.

“When leptin comes in and decreases the activity of these target neurons, that allows insulin levels to go up. That insulin can continue to store the fat, and [tell the fly], ‘You can spend energy in different ways,’” Brent said. “But you wouldn't want that system to get out of control because then you're going to develop things like insulin resistance” — which, in humans, is a precursor to type 2 diabetes.

And, Rajan and Brent found the system does appear to have internal safeguards. The number of contacts between the neurons rebounded after a few days. This depended on insulin, suggesting that the circuit designed to facilitate insulin release is also designed to reset itself and reestablish its baseline.

A cellular and molecular basis for a body-weight set point

The resetting of the fat-sensing neural circuit supports the idea that the body is trying to maintain its fat stores at a certain level, Rajan said. How the set point, if it exists, could get reset to a higher level, as some think occurs with long-term weight gain, remains an open question.

“These neural circuits are meant for sort of a flexibility,” Brent said. “It may be that problems arise when they're always seeing a surplus, and we don't allow them to have the sort of up and down cycle. You can imagine if you allow this to go on long-term so that you're always giving them the surplus nutrition, you might now be reestablishing that set point at a higher level.”

This work was funded by the National Institutes of Health.