There’s more to those love handles than meets the eye. Fat tissue can communicate with other organs from afar, sending out tiny molecules that control gene activity in other parts of the body, according to a new study. This novel route of cell-to-cell communication could indicate fat plays a much bigger role in regulating metabolism than previously thought. It could also mean new treatment options for diseases such as obesity and diabetes.
“I found this very interesting and, frankly, very exciting,” says Robert Freishtat of Children’s National Health System in Washington, D.C., a pediatrician and researcher who has worked with metabolic conditions like obesity and diabetes. Scientists have long known that fat is associated with all sorts of disease processes, he says, but they don’t fully understand how the much-reviled tissue affects distant organs and their functions. Scientists have identified hormones made by fat that signal the brain to regulate eating, but this new study—in which Freishtat was not involved—takes a fresh look at another possible messenger: small snippets of genetic material called microRNAs, or miRNAs.
MiRNAs, tiny pieces of RNA made inside cells, help control the expression of genes and, consequently, protein production throughout the body. But some tumble freely through the bloodstream, bundled into tiny packets called exomes. There, high levels of some miRNAs have been associated with obesity, diabetes, cancer, and cardiovascular disease.
To understand how miRNAs function in fat, a team of researchers led by Thomas Thomou, a diabetes researcher at Joslin Diabetes Center and Harvard Medical School in Boston, studied a genetically engineered strain of mice in which fat cells lacked a critical miRNA-processing enzyme. These rodents had less fat tissue, and they couldn’t process glucose as effectively as nonengineered mice. They also had low circulating miRNA levels overall, suggesting that most of the miRNAs in exosomes come from fat tissue, the researchers reported this week in Nature.
By transplanting fat from normal mice, the researchers restored the previously low miRNA levels in the modified mice. Transplants of brown fat—specialized energy-burning fat that regulates temperature—helped restore glucose processing in the genetically modified mice, whereas white fat—energy-storing fat—transplants did not.
In a previous study with the mice whose fat had impaired miRNA production, the researchers also noticed that other organs—including the heart and liver—were affected, even though the genetic modification didn’t alter those tissues directly. So they decided to investigate whether fat uses miRNAs to communicate with other tissues, Thomou says. They developed a method to measure cross-talk using a human miRNA. In one group of mice, they engineered brown fat cells to produce the human miRNA and package it in exosomes; in another, they engineered liver cells to produce a fluorescent molecular target for the miRNA. Injecting exosomes from the first group of mice into mice from the second group caused a drastic drop in liver cell fluorescence, because the miRNA bound to the fluorescent target and suppressed its production. This confirmed that fat tissue, through exosomes, can communicate with the liver and regulate gene expression. Exosomal miRNAs from brown fat were also found to regulate expression of an important metabolism gene, Fgf21, in liver cells.
“This finding will provide not only insights into new pathways of tissue communication, but also pathways that can be altered in disease states,” says study co-author C. Ronald Kahn, a diabetes researcher and physician at Harvard University. If researchers can figure out how to engineer exomes to target specific cell types, adds Thomou, they might one day use the vesicles to deliver drugs and other therapies. But it’s far from clear, he notes, whether exomes target specific cell types—using a kind of “molecular ZIP code” that could help them travel from point A to point B.
Thomou and his team plan to continue identifying specific miRNA signatures from different tissues to determine what other factors, besides miRNAs, are bundled into exosomes. For Freishtat, the new work offers an exciting way to begin filling a gap between mouse models and human patient studies. “This is a big deal,” he says. “We’re just beginning to scratch the surface of exosomes and how they regulate processes in the body.”