The study reveals a chain linking obesity to unchecked inflammation: obesity inactivates the nucleotide-degrading enzyme SAMHD1, allowing nucleotide buildup that damages mitochondrial DNA and activates the NLRP3 inflammatory complex, driving metabolic disease. Deleting SAMHD1 in mice recreated the same inflammatory and metabolic outcomes. Separately, mRNA packaged in lipid nanoparticles restored embryo attachment after endometrial injury in mice by delivering GM-CSF to the uterine lining, suggesting a new fertility treatment avenue.
Researchers Uncover How Obesity Sparks Runaway Inflammation — New Paths for Treatment
FILE PHOTO: A person walks past cutout silhouettes showing different body shapes at an exhibition on abdominal obesity in Shanghai, China September 22, 2025. REUTERS/Andrew Silver
Researchers have identified a molecular pathway that explains how obesity can trigger uncontrolled inflammation, a process linked to type 2 diabetes, fatty liver disease and other metabolic disorders.
Obesity, SAMHD1 and the NLRP3 Inflammatory Switch
“It has long been observed that obesity leads to runaway inflammation, but the mechanism behind it was unknown. Our study offers new insights into why this happens and how it might be halted,” said study leader Zhenyu Zhong of UT Southwestern.
Previous research showed that infection-free inflammation is often driven by an immune sensor complex called NLRP3, which converts inactive precursor molecules into mature inflammatory signals. In the new study published in Science, investigators compared immune cells from lean and obese human volunteers and from mice fed standard versus high-fat diets.
Cells from obese people and high-fat-fed mice displayed markedly elevated NLRP3 activity. The overactive immune cells contained large amounts of damaged mitochondrial DNA — damage the researchers traced to an excess of nucleotide building blocks. Crucially, the enzyme SAMHD1, which normally degrades nucleotides, had been switched off in these cells.
To test causality, the team deleted the gene for SAMHD1 in mice. Those animals developed the same sequence of events: nucleotide accumulation in immune cells, extensive mitochondrial DNA damage, hyperactive NLRP3 complexes and ultimately inflammation-driven metabolic disease, including insulin-resistant type 2 diabetes and fatty liver.
Zhong and colleagues propose a model in which SAMHD1 inactivation initiates a molecular cascade culminating in obesity-associated inflammation. The findings point to several potential intervention points: preserve SAMHD1 activity, block excess nucleotide transport into mitochondria, or prevent damaged mitochondrial DNA from engaging NLRP3 and triggering inflammatory molecule maturation.
mRNA-LNP Delivery Restores Embryo Attachment In Mice
Separately, a team led by Laura Ensign at Johns Hopkins Medicine reported in Nature Nanotechnology that messenger RNA packaged in lipid nanoparticles (LNPs) can deliver therapeutic instructions to the uterine lining in mice. The LNPs carried mRNA encoding GM-CSF, an immune protein believed to thicken the endometrium and improve embryo attachment.
After infusion, GM-CSF protein levels in the mouse endometrium remained elevated for up to 24 hours. In mice with an endometrial injury designed to mimic human structural causes of implantation failure, the mRNA-LNP treatment restored embryo attachment to levels comparable with healthy controls; untreated injured mice had on average 67% fewer implantation sites.
The researchers plan to test other molecules delivered by the same platform and suggest the approach might eventually be adapted to treat conditions such as endometriosis or endometrial cancer.
Reporting: The obesity-inflammation findings were published in Science; the uterine mRNA work appeared in Nature Nanotechnology. Study leaders noted the results offer multiple avenues for future research but emphasized that clinical applications will require more study and validation in humans.
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