Health Rounds: How obesity leads to uncontrolled inflammation discovered

(This is an excerpt of the Health Rounds newsletter, where we present latest medical studies on Tuesdays and Thursdays.)

By Nancy Lapid

Jan 21 (Reuters) - Researchers say they have finally discovered the pathway by which obesity causes runaway inflammation that can lead to a host of health issues such ​as diabetes and liver disease.

“It’s been known for a long time that obesity causes uncontrolled inflammation, but no one knew the mechanism behind it. ‌Our study provides novel insights about why this inflammation occurs and how we might be able to stop it,” study leader Zhenyu Zhong of UT Southwestern said in a statement.

It was already known that inflammation ‌in the absence of an infection is largely driven by a sensor protein complex in immune cells known as NLRP3, which converts immature inflammatory molecules to mature ones that stimulate inflammation.

When the researchers compared immune cells from lean and obese human volunteers and from mice fed regular and high-fat diets, they found excessive NLRP3 activity in the obese people and the high-fat-consuming rodents, according to a report published in Science.

The immune cells with excessive NLRP3 activity had large amounts of damaged DNA in their mitochondria, the cells’ energy factories, ⁠which the researchers attributed to excessive amounts of DNA building ‌blocks called nucleotides.

The reason for the extra nucleotides is that an enzyme called SAMHD1, which ordinarily degrades the nucleotides, had been turned off, the researchers also discovered.

When they turned off the same enzyme in mice by deleting the gene for it, they created the ‍same inflammatory phenomenon. They saw excess nucleotides in the immune cells, large amounts of damaged DNA in the cells’ energy factories, overactive NLRP3 protein complexes, and eventually, inflammation-related type 2 diabetes and fatty liver disease.

The new findings suggest inflammation in obesity occurs through a molecular cascade kicked off by inactivation of SAMHD1, Zhong said.

The discovery suggests multiple potential approaches researchers could explore to ​prevent such inflammation.

They could look at ways to stop the inactivation of SAMHD1, so that DNA building blocks would not accumulate, for example. Another might be to ‌somehow block the delivery of the extra DNA building blocks to the mitochondria.

A third approach might be to block the damaged mitochondrial DNA from attaching to NLRP3, preventing immune cell maturation.

SENDING FERTILITY INSTRUCTIONS TO THE UTERINE LINING

Using messenger RNA to deliver instructions to the cells that line the uterus might someday lead to new treatments for some forms of infertility, studies in mice suggest.

In particular, the researchers are seeking to improve disorders such as endometriosis that can make embryos less likely to attach to the endometrium, a necessary step for pregnancy to proceed.

Patients who cannot begin or maintain a pregnancy because embryos cannot attach to the uterine lining do not have effective approved ⁠options to turn to, study leader Laura Ensign of Johns Hopkins Medicine said in a statement.

“What ​we’re doing (with our study) is establishing a new standard of care for people to explore,” she said.

Researchers ​used small capsules made of fatty molecules called lipid nanoparticles (LNPs) to deliver the fragile, fast-degrading mRNA molecules to the endometrium.

The LNPs carried genetic code of an immune protein called GM-CSF that is believed to improve embryo attachment by increasing the thickness of the endometrium, the ‍researchers reported in Nature Nanotechnology.

After infusing mice ⁠with the genetic material, the researchers discovered that GM-CSF protein levels in the mouse endometrium remained high for up to 24 hours.

Researchers used the same tailored mRNA-LNP treatment in mice with an endometrial injury similar to what is seen in humans with infertility related to structural issues in the endometrium.

They found embryo attachment ⁠was restored to levels comparable to those in healthy mice, while untreated mice showed 67% fewer embryo implantation sites on average.

The researchers said they will test delivery of other molecules that could potentially ‌improve fertility. They also said their mRNA delivery system could eventually address other disorders, such as endometriosis and endometrial cancer.

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(Reporting by Nancy Lapid; Editing by Bill Berkrot)