Stop Obesity: Preventing Weight Gain is Now Possible With a New Drug ‘CAGE’

A new study from the US has found that the absorption of fats from foodstuffs can be reduced physically, using a liquid salt called Choline and Geranate (CAGE) that is administered orally. The study was carried out in a rat model and was jointly conducted by Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School for Engineering and Applied Sciences (SEAS). The findings, published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), indicated that the administration of CAGE reduced the total body weight of the rats by 12 percent, and no side effects were observed.

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Study Team

The study was led by Dr. Samir Mitragotri, Ph.D., who is a Core Faculty Member at Wyss, as well as the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS. 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.

Dr. Donald 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.

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Obesity and its Implications

Obesity 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, asthma, heart disease, and stroke. Because of this, obesity is considered to be a major public health threat and has reached epidemic proportions in many parts of the globe.

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 are also available that can lower body weight by about 10 percent. However, these drugs exhibit a wide range of side effects, including headache, diarrhea, sleep apnea, hepatotoxicity, pancreatitis, birth defects, and suicidal tendencies.

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.

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Objective of the Study

The primary objective of the study was 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, discussed below.

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,” said Mitragotri.

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 diet 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 following treatment.

Future Plans

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,” said Mitragotri.

Ingber concludes: “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.”

References:

1. Oral Ionic Liquid for the Treatment of Diet-induced Obesity - (https://www.pnas.org/content/early/2019/11/19/1914426116)
2. Locking Up Fats in CAGEs to Treat Obesity - (https://wyss.harvard.edu/news/locking-up-fats-in-cages-to-treat-obesity/)

Source-Medindia