(© sun_apple - stock.adobe.com)

In a nutshell

Having some belly fat may be beneficial for brain health in younger individuals due to its role in maintaining healthy BDNF.

Aging disrupts this benefit because of decreased production of a key protein, CX3CL1. This leads to lower BDNF levels and potentially contributes to cognitive decline.

Excessive fat accumulation, particularly in obesity, is associated with overexpression of 11β-HSD1, which is linked to negative metabolic effects.

TOKYO — Age-related cognitive decline sneaks up on millions of people worldwide. It begins with those frustrating “senior moments” in middle age and can progress to more serious memory and thinking problems later in life. While scientists have traditionally focused their attention directly on the brain to understand these changes, new research out of Toho University in Japan points to an unexpected contributor: your belly fat.

A study published in the journal GeroScience reveals that visceral fat—the deep fat surrounding your internal organs—plays a role in maintaining brain health through a chemical messaging system. You might have heard of BDNF (brain-derived neurotrophic factor)—think of it as brain fertilizer. It helps brain cells grow, survive, and form new connections. The more BDNF you have, the better your brain functions. But as you age, your BDNF levels naturally drop, and that’s when memory problems can start.

Here’s where belly fat comes in. This new study found that CX3CL1, a protein made by visceral fat, plays a big role in maintaining healthy BDNF levels. In younger mice, their belly fat produced plenty of CX3CL1, keeping their brain function strong. But as the mice aged, both their belly fat and their brain’s BDNF levels took a nosedive. When scientists artificially lowered CX3CL1 in young mice, their BDNF levels dropped too, mimicking the effects of aging. But when they gave older mice an extra dose of CX3CL1, their brain’s BDNF bounced back.

These findings flip conventional wisdom about belly fat on its head. While excess visceral fat is still harmful and linked to many health problems, this research suggests that healthy amounts of visceral fat early on serve an important purpose by producing signaling molecules that support brain health.

The research tracked male mice at different ages—5, 10, and 18 months old (roughly equivalent to young adult, middle-aged, and elderly humans). The 5-month-old and 10-month-old mice had similar levels of BDNF in their hippocampus, but by 18 months, these levels had dropped by about a third. This pattern matches the typical trajectory of cognitive aging, where significant decline often doesn’t begin until later in life.

Similarly, CX3CL1 production in visceral fat remained stable in younger mice but declined significantly in older animals, supporting a link between the two proteins.

Scientists show how some visceral fat is beneficial because of its ability to produce CX3CL1. But they stress that too much, of course, is harmful to health — especially for an aging brain.(© suriya – stock.adobe.com) Stress Hormones and the Fat-Brain Connection

To dig deeper, the researchers asked: What causes the drop in fat-derived CX3CL1 in the first place? The answer involved stress hormones like cortisol (in humans) and corticosterone (in mice).

“Glucocorticoids boost CX3CL1 production. An enzyme in belly fat called 11β-HSD1 reactivates inactive forms of glucocorticoids and keeps them active in cells, promoting glucocorticoid-dependent expression of CX3CL1,” study co-author Dr. Yoshinori Takei tells StudyFinds. “11β-HSD1 is essential for belly fat to respond to circulating glucocorticoids properly.”

But as we age, the amount of this enzyme declines, leading to lower CX3CL1 and BDNF levels. When 11β-HSD1 decreases with age, this entire system weakens, potentially contributing to memory loss.

The paper notes that while lower 11β-HSD1 in aging is problematic for CX3CL1 production and brain health, excessive 11β-HSD1 expression is linked to obesity-related diseases. High 11β-HSD1 levels are associated with metabolic syndrome, which is a known risk factor for cognitive decline.

Rethinking Belly Fat

The connection between belly fat and brain health highlights how intertwined our body systems really are. Our brains don’t operate in isolation but depend on signals from throughout the body—including, surprisingly, our fat tissue.

Before you start thinking about packing on belly fat for the sake of your brain, don’t! The researchers stress that balance is key. Too little belly fat and you lose the brain-protecting effects, but too much can cause serious health problems.

The best way to maintain brain health as you age is to focus on proven strategies: staying active, eating a balanced diet, managing stress, and keeping your mind engaged.

While this research is still in its early stages and was conducted in mice, it opens up fascinating possibilities for understanding how our bodies and brains are connected. Scientists may one day find ways to tap into this fat-brain communication system to slow cognitive decline and keep our minds sharper for longer.

The next time you pinch an inch around your middle, remember: there’s a conversation happening between your belly and your brain that science is just beginning to understand.

Paper Summary How the Study Worked

The researchers used male mice of three different ages: 5 months (young adult), 10 months (middle-aged), and 18 months (elderly). They measured BDNF protein levels in the hippocampus using a test called ELISA that can detect specific proteins in tissue samples. They also measured CX3CL1 levels in visceral fat tissue using two methods: one that detects the RNA instructions for making the protein and another that detects the protein itself. To determine whether fat-derived CX3CL1 directly affects brain BDNF, they used a technique called RNA interference to reduce CX3CL1 production specifically in the belly fat of younger mice, then checked what happened to brain BDNF levels. They also injected CX3CL1 into older mice to see if it would restore their brain BDNF levels. To understand what regulates CX3CL1 production, they treated fat cells grown in the lab with different stress hormones. Finally, they measured levels and activity of the enzyme 11β-HSD1 in fat tissue from younger and older mice, and used RNA interference to reduce this enzyme in younger mice to see how it affected the fat-brain signaling system.

Results

The study uncovered several key findings. First, hippocampal BDNF levels were similar in 5-month-old and 10-month-old mice (about 300 pg BDNF/mg protein) but dropped by about one-third in 18-month-old mice (about 200 pg BDNF/mg protein). CX3CL1 levels in visceral fat showed a similar pattern, decreasing significantly in the oldest mice. When the researchers reduced CX3CL1 production in the belly fat of younger mice, their brain BDNF levels fell within days, similar to levels seen in naturally aged mice. On the flip side, a single injection of CX3CL1 into the abdominal cavity of older mice boosted their brain BDNF back up, confirming the connection between these proteins. The researchers also found that natural stress hormones (corticosterone in mice, cortisol in humans) increased CX3CL1 production in fat cells, while the enzyme 11β-HSD1 that activates these hormones was much less abundant in the fat tissue of older mice. When they reduced this enzyme in younger mice, both fat CX3CL1 and brain BDNF levels decreased, revealing another link in the signaling chain. Together, these results mapped out a communication pathway from belly fat to brain that becomes disrupted with age.

Limitations

While the study presents intriguing findings, several limitations should be kept in mind. The research used only male mice to avoid complications from female hormonal cycles, so we don’t know if the same patterns exist in females. The sample sizes were small, with most tests using just three mice per group. While this is common in basic science research, larger studies would strengthen confidence in the results. The researchers demonstrated connections between fat tissue signals and brain BDNF levels but didn’t directly test whether these changes affected the mice’s memory or cognitive abilities, though their previous work had shown that CX3CL1 injections improved recognition memory in aged mice. The study was also limited to specific ages in mice, and we don’t yet know how these findings might translate to humans across our much longer lifespan. Finally, the researchers used artificial RNA interference techniques to reduce CX3CL1 and enzyme levels for short periods—different from the gradual changes that occur during natural aging—which might affect how the results apply to real-world aging.

Discussion and Takeaways

This research reveals a previously unknown communication system between belly fat and the brain. Under normal conditions, stress hormones in the blood are activated by the enzyme 11β-HSD1 in visceral fat, which then produces CX3CL1. This fat-derived CX3CL1 signals through immune cells and the vagus nerve (a major nerve connecting internal organs to the brain) to maintain healthy BDNF levels in the hippocampus. As we age, reduced 11β-HSD1 in belly fat disrupts this signaling chain, contributing to lower brain BDNF and potentially to age-related memory problems. This discovery changes how we think about visceral fat, suggesting that while excess belly fat is harmful, healthy amounts serve important functions in supporting brain health. The findings also hint at future therapeutic possibilities—perhaps treatments could target components of this pathway to maintain brain function in aging. The researchers note that a careful balance is needed, as both too little 11β-HSD1 (associated with cognitive decline) and too much (linked to obesity and metabolic problems) appear harmful. For the average person concerned about brain health, this research underscores that the body works as an interconnected whole, with tissues we don’t typically associate with thinking—like fat—playing important roles in maintaining our cognitive abilities.

Funding and Disclosures

The study was supported by grants from the Japan Society for the Promotion of Science (JSPS KAKENHI). The lead researcher, Yoshinori Takei, and two colleagues received research funding through grants numbered 23K10878, 23K06148, and 24K14786. The researchers declared no competing interests, meaning they didn’t have financial or other relationships that might have influenced their research or how they reported it.

Publication Information

The paper “Adipose chemokine ligand CX3CL1 contributes to maintaining the hippocampal BDNF level, and the effect is attenuated in advanced age” was written by Yoshinori Takei, Yoko Amagase, Ai Goto, Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Akira Hirasawa, and Atsushi Sugiyama from Toho University and other Japanese institutions. It appeared in the journal GeroScience in February 2025, after being submitted in October 2024 and accepted for publication in January 2025. The paper can be accessed online using the identifier https://doi.org/10.1007/s11357-025-01546-4.

Before you start thinking about packing on belly fat for the sake of your brain, don’t! The researchers stress that balance is key. Too little belly fat and you lose the brain-protecting effects, but too much can cause serious health problems. The best way to support your brain as you age is to focus on proven strategies: staying active, eating a balanced diet, managing stress, and keeping your mind engaged.

While this research is still in its early stages and was conducted in mice, it opens up fascinating possibilities for understanding how our bodies and brains are connected. Scientists may one day find ways to tap into this fat-brain communication system to slow cognitive decline and keep our minds sharper for longer.

So, the next time you look at your belly, remember: there’s a secret conversation happening between your fat and your brain, and science is just beginning to understand it.

Funding and Publication Information

The study was supported by grants from the Japan Society for the Promotion of Science. The researchers declared no competing interests.

The paper “Adipose chemokine ligand CX3CL1 contributes to maintaining the hippocampal BDNF level, and the effect is attenuated in advanced age” was written by Yoshinori Takei and colleagues from Toho University and other Japanese institutions. It appeared in the journal GeroScience in January 2025, after being submitted in October 2024 and accepted for publication in January 2025.