The first author
of the study was Dr. Md Nurunnabi, Ph.D., who is
currently an Assistant Professor of Pharmaceutical Sciences at the University
of Texas at El Paso. He was a Postdoctoral Fellow at the Wyss Institute and
SEAS at the time of the study.
Ingber, MD, Ph.D., who is the Founding Director of the Wyss Institute
for Biologically Inspired Engineering, was on the study's advisory board.
Dr. Ingber also holds multiple appointments as 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.
Obesity and its Implications
occurs due to excess deposition of body fat
and affects over one-third of all adults in the US. It is primarily caused by
overconsumption of a high-calorie diet that is rich in fats and carbohydrates,
although it has been found that genetic factors also play a role. Obesity can
lead to several potentially life-threatening diseases, such as diabetes, hypertension
, heart disease
, and stroke. Because of this,
obesity is considered to be a major public health
and has reached epidemic proportions in many parts of the
A healthy, balanced
diet is recommended by doctors to tackle obesity. Besides this, several USFDA
(United States Food and Drug Administration) approved weight-lowering drugs
available that can lower body weight by about 10 percent. However, these drugs
exhibit a wide range of side effects, including headache
, sleep apnea, hepatotoxicity
, birth defects, and suicidal
It is predicted
that the financial burden of managing obesity is likely to double every coming
decade, which will account for approximately 16 percent of healthcare costs in
the US by 2030.
Objective of the Study
objective of the study is to reduce the body weight of obese individuals by
approximately 12 percent, through the development of novel drugs, based on the
translation of the findings of the in vivo
rat model studies,
Discovery and Importance of CAGE
CAGE was discovered
several years ago by Mitragotri and his group, when they were trying to improve
the absorption of drugs by the body. They subsequently found that CAGE
significantly improved the absorption of orally administered insulin. During
their investigation, Mitragotri and his team identified a small hydrophobic
molecule to which CAGE was capable of binding, thereby preventing it from being
absorbed. "That observation led us to wonder if there were any contexts in which
we would want to prevent the uptake 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,"
CAGE: In Vitro Studies
The research team
carried out in vitro
studies to evaluate
the interaction of CAGE with fat molecules. When CAGE was mixed with an omega-3-fatty acid
known as docosahexanoic acid
(DHA), large particles of DHA were formed that were 3-4 microns in length,
which approximated the size of a cell's nucleus. However, when DHA molecules
were mixed with only water, much smaller particles (50-400 nanometers) were formed.
This indicated that DHA must be interacting with CAGE, which resulted in the
formation of large aggregates having dimensions in the micrometer range.
When the DHA-CAGE
mixture was added ex vivo
to healthy rat
intestines, the CAGE significantly inhibited the absorption of DHA into the
intestinal tissue over a period of 6 hours. This was, however, not observed
when DHA was injected alone.
CAGE: In Vivo Studies
In the in vivo
rat model studies, capsules containing a
mixture of DHA and CAGE were administered orally into the rats. It was observed
that the amount of DHA absorbed into the blood over a period of 6 hours was
approximately half that when DHA was administered without CAGE.
When DHA was
administered along with CAGE, it was concentrated more than two-fold in the
stomach and intestine, compared to that in the liver. This indicated that CAGE
prevented the DHA from leaving the gastrointestinal (GI) tract.
The effect of CAGE
on fat absorption in rats fed on a high-fat
was then studied. This high-fat diet - fed over a period of 30
days - contained 20 percent more fat than a normal diet. Rats on a high-fat
diet that received a 10 microliter dose of CAGE daily, gained 12 percent lesser
weight, compared to rats that received either a 5 microliter dose of CAGE or no
CAGE at all. It was further observed that untreated rats ate approximately 10 g
of food daily, whereas the CAGE-treated rats ate only 8 g of food. This
suggested that CAGE could be having an effect on digestive enzymes that
regulate satiety or a feeling of fullness following a meal
There were no side
effects or signs of inflammation or abnormalities in the structure and function
of the organs in the CAGE-treated rats over the entire 30-day period of the
study. Moreover, there were no traces of CAGE in the body tissues of the rats
The research team
is planning to translate the work to develop new drugs that could help people
maintain a healthy body weight. They also plan to study the mechanism of
binding of CAGE to fat molecules, how long the effects last, and where the
unabsorbed fats go. They will also investigate how CAGE influences the leptin
signaling pathway that is intricately associated with obesity.
Concluding Remarks"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,"
"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."
- Oral Ionic Liquid for the Treatment of Diet-induced Obesity - (https://www.pnas.org/content/early/2019/11/19/1914426116)
- Locking Up Fats in CAGEs to Treat Obesity - (https://wyss.harvard.edu/news/locking-up-fats-in-cages-to-treat-obesity/)