Junk DNA in fat cells plays a role in obesity

Researchers have identified thousands of molecules—produced by the genome’s “junk” DNA—that are found only in human fat cells and play an important role in how we store and use fat. The finding, published in Science Translational Medicine, could lead to better treatments for obesity and other metabolic disorders.

Knowing that humans and mice share many of the same genes, previous studies of fat regulation have relied on studies of mice. But few discoveries made in mice have been successfully translated into therapies for human metabolic disorders.

That may be because humans and mice are not as genetically similar as we thought. Although the two species share 92 percent of their protein-making genes, the vast majority of the genome does not code for proteins. Researchers in the past had mostly dismissed this portion of the genome as “junk” DNA with no discernible purpose.

“But more and more evidence suggests that it’s not junk at all, and parts of it are very different between humans and mice,” says the senior author. “It raises the question: Are these parts of the genome, not found in mice, doing something in people?”

To see if “junk” DNA plays a different role in human fat cells than in mice fat cells, the team focused on a large portion of the genome that creates molecules called long intergenic non-coding RNAs, or lincRNAs, which evolved rapidly and are very different between mice and humans. LincRNAs were only discovered within the past decade, but it’s now known there are likely tens of thousands of them in humans.

Using unusually thorough techniques to detect RNA molecules, the team analyzed fat tissue from 25 healthy, lean participants. Their analysis identified more than 4,000 different lincRNAs, of which 85 percent are not found in mice. Of these, 1,001 molecules were shared among all of the participants.

One hundred twenty lincRNAs had adipose-enriched expression, and 54 of these exhibited peroxisome proliferator–activated receptor γ (PPARγ) or CCAAT/enhancer binding protein α (C/EBPα) binding at their loci. Most of these adipose-enriched lincRNAs (~85%) were not conserved in mice, yet on average, they showed degrees of expression and binding of PPARγ and C/EBPα similar to those displayed by conserved lincRNAs. Most adipose lincRNAs differentially expressed (n = 53) in patients after bariatric surgery were nonconserved.

Not all lincRNAs have a function, but the researchers found signs that many of the lincRNAs unique to humans had features that suggest they also may contribute to fat regulation. The researchers took a close look at the most abundant one—linc-ADAL, which is not found in mice and had never been studied before—and found that it plays a significant role in how fat cells develop and how they store fat.

Authors show that linc-ADAL interacts with heterogeneous nuclear ribonucleoprotein U (hnRNPU) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) at distinct subcellular locations to regulate adipocyte differentiation and lipogenesis.

The team also discovered subsets of lincRNAs that were expressed differently in males and females and others that were expressed differently in people who had undergone bariatric surgery. These characteristics suggest potential roles for these lincRNAs in observed sex differences in fat storage as well as in obesity and its complications.

But because mice don’t have the same lincRNAs as humans, new and more sophisticated model systems are needed to translate these findings into knowledge of diseases in humans and more effective therapies for metabolic diseases.

“We need more creative approaches to move forward, such as using human organoids [miniature lab-grown tissue structures that mimic many of the characteristics of actual organs], mouse models that are engineered to incorporate human DNA or can reconstitute human tissues and organs, and advanced human genetics and bioinformatics that can help to implicate roles for specific lincRNAs in human disease,” senior author says. These approaches are both technically challenging and more expensive to implement than traditional mouse model approaches.

Emerging studies have found that human-specific lincRNAs are abundant in all tissues, as well as in tumors, potentially opening a wholly new approach to the study of disease and development of new therapies. Each of these tissues has its own set of lincRNAs, which will certainly complicate research and drug development because each tissue will need to be studied individually. “But this heterogeneity is also a good thing,” senior author says. “Because lincRNAs are tissue-specific, drugs that target lincRNAs found in one type of tissue are unlikely to affect other tissues.”

“Most scientists have ignored lincRNAs that differ between humans and mice,” senior author adds. “The very large number of potentially functional human lincRNAs not found in mice goes against the longstanding belief that if a part of the genome isn’t conserved across species—from fruit flies to mice to humans—it is probably not important.

“But more and more, it’s looking like lincRNAs are part of the reason why we are different from mice and other animals and they may be unique contributors to human diseases as well as human characteristics. And what was once considered junk DNA may well hold exciting new keys to the development of effective therapies for metabolic diseases.”