Medical Bulletin 23/December/2025

Fatty liver disease is often linked to obesity, but millions of lean people also develop it unnoticed, making its root causes a mystery. To solve this puzzle, Dr. Charles Brenner, head of the Diabetes and Cancer Metabolism Program at City of Hope, studied citrin deficiency as a model. CD patients share two curious traits: they remain lean yet have fatty livers, and they instinctively avoid sweets and alcohol. Brenner’s team suspected the liver’s stress response might drive both effects.

Using molecular and metabolic models, researchers discovered that when the liver lacks citrin, levels of the molecule glycerol 3 phosphate (G3P) surge. This buildup activates ChREBP, a protein that flips on genes responsible for producing and storing fat, effectively programming the liver to accumulate rather than burn fat. At the same time, G3P acts as a stress signal that triggers higher levels of FGF21, a hormone known to suppress cravings for sugar and alcohol while promoting fat metabolism.

The dual action of G3P—fueling fat buildup but also prompting hormonal self correction—helps explain why lean people with CD develop fatty livers yet shun sweet foods. It also provides a missing link between metabolic stress, diet behavior, and liver health.

These findings point to promising therapeutic targets. Drugs that block the G3P–ChREBP pathway could reduce fat synthesis in the liver, while G3P based or FGF21 mimicking therapies might help regulate appetite and enhance fat burning. “By understanding how metabolism goes awry, we can design smarter ways to restore balance,” said Dr. Brenner.

With fatty liver disease now affecting over a billion people globally, this discovery could reframe how researchers—from metabolic biology to nutrition science—approach one of today’s fastest growing health crises.

REFERENCE: Tiwari, V., et al. (2025). Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency. Nature Metabolism. DOI: 10.1038/s42255-025-01399-3. https://www.nature.com/articles/s42255-025-01399-3

Specific gut bacterium found to curb weight gain and boost metabolism

It turns out that one tiny gut bacterium might hold big answers for weight control. In a groundbreaking study published in Cell Metabolism, researchers from the University of Utah discovered that a microbe called Turicibacter can improve metabolic health and prevent weight gain in mice, even when they eat a high fat diet. People with obesity tend to have lower levels of this bacterium, hinting at its potential role in maintaining a healthy weight in humans too.

The gut microbiome—a microscopic ecosystem of bacteria and fungi—affects nearly every aspect of health, from digestion to mood. Differences in its composition have been linked to obesity, diabetes, and inflammation. But pinpointing which specific microbes matter most has long been a challenge. “It’s like finding a needle in a haystack,” explained Dr. Kendra Klag, first author of the study, who spent years growing individual bacterial species under oxygen free conditions since most gut bacteria can’t survive outside the body.

The eureka moment came when Dr. Klag identified Turicibacter, a rod shaped bacterium that alone could transform metabolism. In controlled experiments, mice fed Turicibacter gained less weight, had lower blood sugar, and stored less fat than those without the bacterium—even when both groups ate identical high fat diets. The microbe achieved these effects by producing unique fat like molecules that get absorbed by the gut and influence how the body processes lipids. When the researchers fed mice purified versions of these Turicibacter-produced fats, they observed the same slimming and metabolic benefits.

Further experiments revealed a fascinating biochemical feedback loop. A high fat diet normally raises levels of ceramides, fatty molecules associated with insulin resistance and heart disease. But Turicibacter fats kept ceramide levels low, protecting against these metabolic changes. Intriguingly, Turicibacter itself struggles to thrive when too much dietary fat is present—meaning a fatty diet can wipe out the very microbes that protect the body from fat overload.

While these findings are from animal studies, the implications are profound. Future research will focus on identifying the exact “lipid signals” responsible for these benefits, which could inspire new probiotics or microbial-based therapies for obesity and metabolic disorders. As senior author Dr. June Round put it, “Microbes are the ultimate untapped resource in drug discovery. We’re only beginning to understand what these hidden partners can do for us.”

REFERENCE: Klag, K., et al. (2025). Dietary fat disrupts a commensal-host lipid network that promotes metabolic health. Cell Metabolism. DOI: 10.1016/j.cmet.2025.10.007. https://www.sciencedirect.com/science/article/pii/S1550413125004413?via=ihub

Study finds sugar-free sweeteners could negatively impact liver health

They’re sold as diet-friendly, “guilt free” sugar alternatives—but a new study suggests one common sweetener may not be so harmless after all. Research from Washington University in St. Louis, published in Science Signaling, reveals that sorbitol, a widely used sugar alcohol found in sugar free gums and candies, may behave much like fructose, the natural sugar long linked to fatty liver disease and metabolic disorders. The findings challenge decades of assumptions about sugar substitutes and raise new questions about how they affect the liver and metabolism.

Sweeteners like aspartame (Equal), sucralose (Splenda), and sugar alcohols such as sorbitol and xylitol are marketed as safer ways to enjoy sweetness without spiking blood sugar. But the new study, led by Dr. Gary Patti, Professor of Chemistry and Medicine at WashU, shows how the body may actually convert sorbitol into harmful fructose derivatives—potentially undermining the very purpose of using these substitutes in the first place.

Using zebrafish models, Patti’s team discovered that enzymes in the gut can naturally produce sorbitol from glucose after a meal, even in people without diabetes. From there, sorbitol travels to the liver, where it is transformed into fructose like molecules. While this pathway had been recognized in diabetic conditions before, the new study shows it can occur under normal metabolic circumstances, meaning sorbitol’s effects may extend beyond people with high blood sugar.

The researchers also found that gut bacteria play a crucial protective role. Strains of Aeromonas can break down sorbitol into harmless byproducts—but not everyone has these microbes in abundance. When beneficial bacteria are missing or overwhelmed, excess sorbitol reaches the liver, increasing the likelihood of fat accumulation and metabolic stress.

At low concentrations—such as those found in fruits—sorbitol is generally safe. Problems arise when glucose or sorbitol intake is excessive, as gut microbes can’t keep up. This imbalance can push sorbitol metabolism into overdrive, contributing to fatty liver changes and systemic inflammation.

According to Dr. Patti, “there is no free lunch” when it comes to artificial sweeteners. Even sugar alcohols thought to pass harmlessly through the body can end up influencing the same pathways as sugar itself. The study suggests a need for reevaluating “sugar free” labeling and understanding how both diet and microbiome diversity shape our metabolic health.

REFERENCE: Madelyn M. Jackstadt, Ronald Fowle-Grider, Mun-Gu Song, Matthew H. Ward, Madison Barr, Kevin Cho, Hector H. Palacios, Samuel Klein, Leah P. Shriver, Gary J. Patti. Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria. Science Signaling, 2025; 18 (910) DOI: 10.1126/scisignal.adt3549