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Giving fat cell messages a positive spin

Woman on a scale

Study findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that detrimental effects of carrying too much weight can recede. (Image source: Centers for Disease Control and Prevention)

Losing weight appears to reset the chemical messages that fat cells send to other parts of the body that otherwise would encourage the development of Type 2 diabetes, substantially reducing the risk of that disease, a team led by Children’s National Health System researchers report in a new study. The findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that many of the detrimental effects of carrying too much weight can recede, even on the molecular level, once they lose weight.

In 2015, Robert J. Freishtat, M.D., M.P.H., Chief of Emergency Medicine at Children’s National and Associate Professor of Pediatrics, Emergency Medicine and Integrative Systems Biology at The George Washington University School of Medicine & Health Sciences, and colleagues showed that fat cells (also known as adipocytes) from people who are obese send messages to other cells that worsen metabolic function. These messages are in the form of exosomes, nanosized blobs whose contents regulate which proteins are produced by genes. Exosomes are like “biological tweets,” Dr. Freishtat explains — short signals designed to travel long distances throughout the body.

Dr. Freishtat’s earlier research showed that the messages contained in exosomes from patients who are obese alter how the body processes insulin, setting the stage for Type 2 diabetes. However, says Dr. Freishtat, it has remained unclear since that publication whether these aberrant messages from adipocytes improve after weight loss.

“We’ve known for a long time that too much adipose tissue is bad for you, but it’s all moot if you lose the weight and it’s still bad for you,” he explains. “We wanted to know whether these negative changes are reversible. If you reduce fat, does the disease risk that goes along with excess fat also go away?”

Details of the study

To investigate this question, Dr. Freishtat and colleagues worked with six African American adults scheduled to receive gastric bypass surgery — a nearly surefire way to quickly lose a large amount of weight. The volunteers, whose average age was 38 years, started out with an average body mass index (BMI) of 51.2 kg/m2. (The Centers for Disease Control and Prevention considers a healthy BMI to range between 18.5 to 24.9.)

Two weeks before these volunteers underwent surgery, researchers collected blood samples and took a variety of measurements. The researchers then performed a repeat blood draw and measurements one year after the surgery took place, when the volunteers’ average BMI had dropped to 32.6.

Dr. Freishtat and colleagues drew out the adipocyte-derived exosomes from both sets of blood samples and analyzed their contents. The team reports in the January 2017 issue of Obesity that at least 168 microRNAs — the molecules responsible for sending specific messages — had changed before and after surgery. Further analyses showed that many of these microRNAs were involved in insulin signaling, the pathways that the body uses to regulate blood sugar. By changing these outgoing microRNAs for the better, Dr. Freishtat says, adipocytes actively were encouraging higher insulin sensitivity in other cells, warding off Type 2 diabetes.

Sure enough, each volunteer had better insulin sensitivity and other improved markers of metabolic health post-surgery, including lower branched chain amino acids and a two-fold reduction in their glutamate to glutamine ratio.

“These volunteers were essentially cured of their diabetes after surgery. The changes we saw in their surgery-responsive microRNAS correlated with the changes we saw in their metabolic health,” Dr. Freishtat says.

A glimpse into the future

Dr. Freishtat and colleagues plan to study this phenomenon in other types of weight loss, including the slower and steadier paths that most individuals take, such as improving diet and doing more exercise. The team expects to see similar changes in exosomes of patients who lose weight in non-surgical ways.

By further examining the aberrant messages in microRNAs being sent out from adipocytes, he says, researchers eventually might be able to develop treatments to reverse metabolic problems in overweight and obese patients before they lose the weight, improving their health even before the often challenging process of weight loss begins.

“Then, if you can disrupt this harmful signaling in combination with weight-loss strategies,” Dr. Freishtat says, “you’re really getting the best of both worlds.”

Eventually, he adds, tests might be available so that doctors can warn patients that their fat cells are sending out harmful messages before disease symptoms start. By giving patients an early heads up, Dr. Freishtat says, patients might be more likely to heed advice from physicians and make changes before it’s too late.

“If doctors could warn patients that their fat is telling their blood vessels to fill up with plaque and trigger a heart attack in 10 to 20 years,” he says, “patients might be more compliant with treatment regimens.”

Robert J. Freishtat

A game changer for detecting complications from obesity

Robert J. Freishtat

The work that Children’s National Health System physician-scientist Robert J. Freishtat, M.D., M.P.H., and colleagues are doing could soon be a game changer when it comes to early intervention and prevention of obesity-related illnesses.

They already knew there’s a direct relationship between the amount of visceral adipose, or belly fat, a person has and development of some of the most common and life-threatening complications of obesity, including cardiovascular disease and the insulin resistance that leads to diabetes. What remained unclear, until recently, were the precise mechanisms for how the increase in belly fat triggers the onset of additional disease.

Dr. Freishtat, senior author of “Adipocyte-Derived Exosomal miRNAs: A Novel Mechanism for Obesity-Related Disease,” published by Pediatric Research, studies the adipocytes, or fat cells, of visceral adipose in both lean and obese patients to understand exactly how these fat cells can and do wreak havoc — not just locally but throughout the body. Cells leverage exosomes to communicate among themselves, but in overweight patients those cellular communications can go awry.

“As the body’s visceral fat grows, somewhere on the path to obesity the fat cells change and begin to release different exosomes than lean adipose cells do. These new messages disrupt some important processes that eventually prevent the body from effectively dealing with sugar and cholesterol,” says Dr. Freishtat, chief of Emergency Medicine at Children’s National, and associate professor of Pediatrics, Emergency Medicine, and Integrative Systems Biology at the George Washington University.

Dr. Freishtat describes exosomes as “biological tweets”— short messages shed by all cells that allow for intercellular communication and alter gene expression. In the case of the adipocytes that exist in large quantities of visceral fat, these “tweets” actually cause the downregulation of proteins impacting two key signaling pathways — TGF-β and Wnt/β-catenin — associated with controlling chronic inflammation and fibrotic disease throughout the body. These signaling changes make morbidly obese patients more vulnerable to systemwide issues, such as cholesterol accumulation and changes to how the liver processes fat.

Details of the study

The study authors surgically collected fat tissue from lean and obese female patients aged 11 to 19 and used modified bead-based flow cytometry to separate, identify, and compare the exosomal RNA shed by the fat cells in both lean and obese samples. To confirm the unique impact of the obese adipose exosomes on gene expression, the research team then exposed lung cells in vivo to the exosomes shed by both lean and obese adipose. They measured the impact of exposure and uptake on a single receptor type — activin receptor type-2B — known to have a major influence on the TGF-β pathway. The exosomes from obese adipose caused the receptor to slow down, leading to significant changes in the function of the TGF-β pathway.

The team continues to explore how the exosomes shed from excess amounts of visceral adipose spread throughout the body and how the function of organs such as the liver, the heart, and the brain are impacted by the migrating fat cells.

A Look into the future

Successfully identifying and isolating these exosomes also has opened the door to developing a test to detect them, an idea that may permit even earlier intervention to delay or prevent the onset of obesity-related illnesses.

“It is entirely plausible, and is on its way to happening very soon, that someone could walk into their physician’s office for a routine physical and, via a urine test, find out that they are on the road to some dangerous additional side effects of significant weight gain,” says Dr. Freishtat. “That type of early detection could really be a game changer for the millions of Americans who are on track to developing heart, liver, and other diseases resulting from morbid obesity.”