The same white blood cells that rush to fight infection seem to have a second job: preventing your body from burning too much fat.

That’s the finding from a new study published in Nature, which reveals an unexpected partnership between the immune system and fat tissue — one that helped our ancestors survive famine but may now be working against us in an era of abundance.

Researchers at UC San Diego School of Medicine set out to understand how the body prevents excessive fat loss during periods of stress, such as cold exposure or fasting. They knew immune cells change in response to overeating and obesity but wondered what happens on the other side of the equation.

They used a drug to pharmacologically activate the same pathway that cold exposure would trigger in mice. “We basically tried to mimic the effect of cold by activating fat cells with a beta-adrenergic receptor agonist that mimics the sympathetic activation system that you see in cold and also, to some extent, in starvation,” said Alan Saltiel, PhD, professor of pharmacology at UC San Diego School of Medicine and corresponding author of the study.

Within hours of the stress signal, neutrophils — immune cells typically associated with fighting bacteria — flooded into visceral fat, the fat surrounding vital organs. Once there, the neutrophils released interleukin-1-beta (IL-1-beta), a signaling molecule that tells fat cells to slow down lipolysis, the process of breaking down stored fat to release energy.

“We were really surprised to see the neutrophils coming up so fast and to such a large degree, especially in visceral fat,” Saltiel said.

“It was a bit surprising,” said Claudio Villanueva, PhD, professor of integrative biology and physiology at UCLA, who was not involved in the study. “It seemed that the recruitment [of neutrophils] was dependent on lipolysis” — the very process the neutrophils were arriving to slow down.

An Evolutionary Safeguard Gone Awry

From an evolutionary standpoint, this braking mechanism makes sense. When our ancestors faced prolonged cold or food scarcity, burning through fat reserves too quickly could be fatal. The body needed a way to pace itself.

“Our bodies are really designed for survival,” Saltiel said. “Things like cold and starvation — that’s what we’re set up for. Our bodies still have the same sense that there’s a famine around the corner. We are designed to be really efficient at storing energy, and this is one of the ways that we do that.”

The findings may help explain why losing weight is so difficult for people with obesity — and why metabolic dysfunction tends to compound over time.

Villanueva noted that in obesity, baseline lipolysis is already somewhat elevated, with free fatty acids circulating at above-normal levels. “So perhaps in that context, you also will drive recruitment of these neutrophils,” he said. “And then those neutrophils are coming into the adipose tissue, and they’re releasing cytokines that can impact insulin signaling and could potentially contribute to insulin resistance and type 2 diabetes.”

This might create a problematic feedback loop. Insulin normally suppresses lipolysis after eating — when the body has fresh fuel and doesn’t need to tap fat reserves. But when cells become resistant to insulin, that brake weakens, leading to chronically elevated fatty acid release, increased neutrophil recruitment, and more inflammation.

Saltiel noted that individuals respond differently to these processes. “We know that there’s heterogeneity among people in the immune response to obesity, and probably also to cold,” he said. “Some people are more susceptible to it than others.”

A New Drug Target?

The discovery opens the door to potential new treatments. “The important thing we discovered here is that this enzyme in neutrophils makes the cytokine interleukin-1-beta,” Saltiel said. “We think IL-1-beta is a key driver in the fat cell to tell it to slow down lipolysis, to slow down the burning of energy. So, this could be a drug target.”

Several components of the pathway could potentially be targeted, including the inflammasome complex and caspase-1, an enzyme that helps produce IL-1-beta. “Those [molecules] are being targeted by lots of companies now, including in obesity and other inflammatory diseases,” Saltiel noted.

The most intriguing possibility, Saltiel suggested, would be combining such an inhibitor with appetite-suppressing drugs such as GLP-1 agonists. “The idea of combining an anorexic drug with a drug that increases energy expenditure — these are the two things that are balancing obesity, right? Energy in and energy out.”

However, blocking the pathway entirely could carry risks because IL-1-beta plays important roles in immune defense. “You could be concerned about more susceptibility to infection if you completely block the pathway,” Saltiel acknowledged. “But the idea is to just dial it down a little bit. That’s the advantage of using enzyme inhibitors — you have some control, and you can titrate the amount of inhibition that you want.”

A More Complex Picture

Villanueva cautioned that simply suppressing inflammation may not be a silver bullet for metabolic disease. “Inhibitors of inflammation don’t really seem to work robustly for treating metabolic disease. It’s probably more complicated than just suppressing inflammation,” he said.

Part of that complexity involves the dual nature of fat tissue itself. Villanueva pointed out that having too little fat is just as dangerous as having too much. “There are people that don’t have any fat tissue, that are lipodystrophic, and they have severe metabolic disease,” he added.

The neutrophil braking system also serves a protective function: preventing runaway lipolysis that could flood the bloodstream with fatty acids and overwhelm the liver. “When you have unmitigated lipolysis, that will essentially drive more triglycerides and more lipids in the liver,” Villanueva said. “The liver basically starts to become steatotic — it accumulates triglycerides. You do want to suppress that response over time.”

What’s Next?

Saltiel said his team is now working to understand the signaling pathways in greater detail. “Neutrophils migrate into adipose tissue, and then when they’re there, they get activated further in situ. We don’t really understand that — how are they getting activated, and what does that activation look like?”

The researchers also want to explore whether there are additional feedback loops at play. “There’s always a loop in biology — always a feedback loop and a feed-forward loop,” Saltiel said. “We’re trying to understand what else could be going on.”

For now, the study offers a new lens through which to view the frustrating biology of weight loss: The immune system, it turns out, may not just be protecting us from pathogens. It could also be protecting our fat stores — whether we want it to or not.

The study authors declared no competing interests.