which affects more than one-third of American adults, is more than just an uncomfortable excess of weight, it is a driver of several, often fatal diseases like high blood pressure, diabetes
, asthma, stroke, and congestive health failure, making it one of the most significant public health threats. The cost of treating and managing obesity-related diseases is expected to double every decade, ballooning to account for about 16% of all US healthcare costs by 2030.
Although genetics plays a role, eating high-calorie foods rich in carbohydrates and fats is a major cause of this epidemic, and though doctors and nutritionists recommend a healthy, balanced diet as a prevention strategy, many people simply lack affordable access to fresh foods. Several weight-loss drugs that reduce weight by about 10% have been approved by the FDA over the last few decades, but they come with significant side effects including headaches, diarrhea, severe liver injury, birth defects, sleep apnea, pancreatitis, and suicidal thoughts.
A new study from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School for Engineering and Applied Sciences (SEAS) has found that an orally administered liquid salt
called Choline and Geranate
can physically reduce the absorption of fats from food with no discernible side effects in rats, and decreases total body weight by about 12% when a high-fat diet is consumed. The research is reported in PNAS
First author Md Nurunnabi, Ph.D., a former Postdoctoral Fellow at the Wyss Institute and SEAS who is now an Assistant Professor of Pharmaceutical Sciences at The University of Texas at El Paso told Thailand Medical
News, “A reduction in body weight of 12% is like getting a human from 200 pounds down to 176, which is a significant change “Our goal is to translate this work into a product that can help people maintain a healthier weight, and this study marks the very beginning of that journey.”
Choline and Geranate
) which is a salt
in its liquid
state, was created a few years ago by Wyss Core Faculty member Dr Samir Mitragotri, Ph.D. as part of an effort to improve the body’s absorption of medicines. Last year, his lab published a paper describing CAGE
’s ability to enhance the uptake of insulin when given orally. However, in their study of CAGE
’s properties, they found that there was one particular molecule whose uptake was not helped by the liquid: a small hydrophobic molecule. Dr Mitragotri’s team had a hunch that CAGE
was somehow binding to this molecule and preventing it from being absorbed.
Dr Mitragotri, who is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS commented, “That observation led us to wonder if there were any contexts in which we would want to prevent the upta
ke of this type of molecule. We realized that fats are small and hydrophobic, and that CAGE
could potentially be of interest as a medical treatment for obesity
The medical researchers got to work evaluating CAGE
’s interactions with fats by mixing the liquid with an omega-3 fat called DHA and water. They saw that the DHA formed large particles about 3-4 microns in length, about the size of a cell’s nucleus. DHA molecules mixed with water alone formed much smaller particles in the range of 50-400 nanometers, suggesting that there is some interaction between the CAGE
and DHA molecules that causes them to aggregate into larger particles.
The research team then added the DHA-CAGE
mixture to healthy rat intestines ex vivo
. Compared to intestines that were only injected with DHA, the inclusion of CAGE
significantly reduced the permeation of DHA into the intestinal tissue over the course of six hours.
To assess the performance of CAGE
in living organisms, the researchers prepared capsules with a mixture of DHA and CAGE
and gave them orally to rats. After six hours, the amount of DHA absorbed into their blood from the mixture was about half the amount that was absorbed when they were given DHA alone. Biodistribution studies showed that giving CAGE
along with the DHA increased its concentration in the rats’ stomachs and intestines two-fold and reduced its presence in their livers, suggesting that CAGE
prevents DHA from leaving the gastrointestinal tract.
The researchers then studied the effect of CAGE
on fat uptake in rats who were fed a high-fat diet, which has 20% more fat than a regular diet, for 30 days. A daily, 10-microliter dose of CAGE
caused rats to gain 12% less weight than rats that received either a 5-microliter dose or no CAGE
. The untreated rats usually ate about 10 grams of food every day, whereas the high-dose CAGE
cohort ate about 8 grams of food, suggesting that CAGE
might also have an effect on enzymes that regulate digestion, and/or increase the feeling of fullness after a meal.
Over the 30-day time period, no side effects were observed in the rats treated with CAGE
, and there were no signs of inflammation or differences in the animals’ organ structure or function. There was also no trace of CAGE
’s components in the body following treatment.
Dr Mitragotri added, “This is the first proof-of-concept that orally administered ionic liquids can help reduce fat uptake and body mass, and this approach has significant clinical potential given that it is simple, fast, and much less invasive than liposuction or bariatric surgery and, because its mechanism of action is physical rather than chemical, it lacks the side effects observed with other drugs.”
The research team is now pursuing answers to the more mechanistic questions about CAGE
, including exactly how CAGE
binds to fats, how long its effects last, what its potential interactions with the obesity-associated leptin signaling pathway are, and where the unabsorbed fat goes.
Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology
at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS said, “This study is a perfect example of the potentially transformative innovations that can come from looking at an unexpected result in the lab as a solution rather than a problem. We love simple solutions here at the Wyss Institute.”
Reference: Nurunnabi, et al. (2019) Oral ionic liquid for the treatment of diet-induced obesity. PNAS DOI: https://doi.org/10.1073/pnas.1914426116