Another look at leptin

Leptin’s heyday

The rise and fall of leptin in the bloodstream tells the brain whether we’re starving or well -fed based on how much fat we’ve managed to set aside.

If fat stores deplete, then leptin levels drop, signaling that food is scarce so snarf it up whenever you find it, which makes us feel hungrier all the time.

If fat stores increase, leptin levels rise, signaling that food is generally abundant, which should make us feel more satiated with each meal and less obsessed about getting the next one.

But in chronic obesity, leptin’s signal loses its potency from overuse and the brain pays less attention to the hormone’s constant pinging, a condition researchers call leptin resistance.

Without an accurate leptin signal, we feel hungry when we’re not really hungry, so we overeat and grow fatter, which produces even more leptin, which the brain ignores even more, making weight loss difficult.

The vicious cycle of leptin resistance dashed the hopes of researchers after the hormone was discovered in the 1990s.

“Just like how everyone is going nuts about Ozempic right now, people went nuts about leptin at the time because they thought: ‘Oh, this is going to solve obesity’,” Rajan said.

It turned out that while injections of leptin can make a difference for people who can’t produce the hormone on their own, extra leptin doesn’t help people who already produce plenty and become leptin-resistant.

As hope faded that leptin would provide the key to an obesity drug, researchers moved on.

Meanwhile, the development of a better drug for diabetes eventually led to Ozempic, which also causes weight loss. 

Ozempic, known generically as semaglutide, mimics a different appetite-regulating hormone than leptin, targeting a similar region of the central brain to inhibit cravings, but with greater success.

What is leptin really telling us?

The modern human struggle with obesity casts leptin’s role negatively as a disciplinarian scolding the brain into saying no to dessert, but Rajan thinks that’s too narrow a view.

Leptin’s message to the brain isn’t “hey, put down the fork!”

It’s more like “hey, you’ve got enough reserves now to get out there and live your best life.”

Think of leptin like the monitor in your phone that tells you how much battery life you have left. When you see that glorious 100%, you can play videos to your heart’s content, but when you get that 15% warning, you have to turn off the videos and close non-essential apps.

High leptin levels tell the brain we have enough energy to do important and fun things in life such as bulking up the immune system and reproducing.

But when leptin levels drop, we can only do what’s necessary for immediate survival.

The journey that led to the study began about 12 years ago when Rajan was a postdoctoral researcher, tinkering around with a gene in fruit flies that encodes a protein like human leptin.

Fruit flies are one of the most common model organisms used in biomedical research because they are inexpensive to maintain, reproduce quickly, and exhibit many fundamental genetic and molecular mechanisms that are similar in humans.

“I found that if you unplugged leptin, if you unplugged that gene, it created a dysregulated metabolic profile in the fly,” Rajan said.

When she injected human leptin back into the fly, it restored function, just like it does for humans who lack a functioning leptin gene.

Rajan was amazed that humans and flies – about 600 million years apart on the great evolutionary tree of life – shared this basic biology.

That discovery opened new experimental possibilities using fruit flies to understand how our bodies respond to the constant ebb and flow between feast and famine at the genetic level.

“It gives you a new tool kit to play with that was absent in the mammalian system,” she said.

Surviving scarcity

Over the next several years, she assembled a team of investigators with different specialties – including the study’s lead co-authors Aditi Madan, PhD, a staff scientist, and Kevin Kelly, PhD, a postdoctoral researcher – to better understand how leptin secretion affects appetite.

They hypothesized that there might be some overlap among proteins that are active when an organism is starving and proteins that are active when an organism is well-fed.

They found that overlap in a protein well-known for its role in triggering autophagy, which occurs when the body literally eats its own cells to generate extra fuel during famine.

The protein, called Atg8 in fruit flies and LC3 in humans, has been scrutinized for many years. It’s also a target for cancer therapy because autophagy also helps recycle cellular materials, a tumor-eating function that often is disrupted in cancer.

The breakthrough came when Rajan’s team discovered that this protein flips a switch when food becomes abundant. Instead of promoting autophagy, it promotes an opposite function: leptin secretion.

When the protein is in self-scavenging mode, it keeps leptin trapped within the cell, which lowers leptin levels in the blood, which tells the brain to find food and fast.

When self-scavenging is no longer necessary, the protein switches jobs and releases the captive leptin, which then tells the brain of a fruit fly or a human that food scarcity is not something to fret about. 

The revelation that a single protein performs opposite functions in times of scarcity and surplus surprised Rajan. She expected that such important functions would have been achieved independently with their own dedicated proteins.

“The idea that it would even do something like secretion was mind-blowing,” Rajan said.

Kelly was shocked as well.

“It makes you wonder what other hidden roles these proteins control that we think we know so much about,” Kelly said.

The team also genetically manipulated some flies to keep leptin in their cells, as if they were in starvation mode, whether they were well-fed or not. They expected that keeping leptin out of circulation would damage their feeding behavior. Instead, they discovered surprising resilience.

“The flies, when you starve them, have superpowers,” Rajan said.

The flies that kept leptin trapped in the cells at all times got hungry when they were supposed to get hungry. They didn’t overfeed when food was available and ate more only when subjected to starvation. Ultimately, those flies survived longer than normal flies.

“In short, there seemed to be no metabolic drawback to keeping the flies in ‘starved’ mode,” Kelly said. “If anything, these flies seemed to outperform normal flies in all of our experiments.” 

Retaining leptin in fat appears to help flies survive better during times of scarcity, which is a far more common experience in the history of our own species than the modern era of 24-hour fast food and all-you-can-eat buffets.

“This study beautifully demonstrates the evolutionary conservation of fat-to-brain signaling circuits between flies and humans,” Madan said. “Information gleaned from upcoming studies will shed light on potential drug targets for metabolic disorders in humans.”

Making leptin louder

Increasing leptin wasn’t the answer to reducing obesity because more leptin pinging the brain somehow made the signal quieter and easier to ignore.

But what if a drug could make less leptin sound louder in the brain, restoring leptin’s signaling function? What if a drug could flip the molecular switch back to starvation mode, locking up leptin within the cell artificially?

Lowering the amount of leptin could get the brain to pay more attention to its signal, breaking the vicious cycle of leptin resistance in chronic obesity.

“It would be interesting to test in the future if Ozempic can synergize with reduced leptin secretion,” Rajan said. “Both Ozempic and leptin act on appetite circuits, but we need to better understand how the two may interact.”

Meanwhile, Rajan and her colleagues want to understand more about what specifically causes the molecular switch to flip, and they’d like to know a lot more about the adaptive superpowers that flies exhibit under the pressure of starvation.

Knowing how it works scientifically hasn’t done much to change Rajan’s own cravings, however.

“My whole interest in studying this is because I just like sweets so much,” Rajan said. “After 12 years, I still go for that candy.”

This work was supported by grants from the National Institutes of Health, Fred Hutch, National Science Foundation Postdoctoral Research Fellowship, the Helen Hay Whitney Foundation (MAA) and the Proteomics, Genomics & Bioinformatics, and Cellular Imaging Shared Resources at Fred Hutch/University of Washington/Seattle Children's Cancer Consortium.