Team develops anti-obesity treatment in animal models

March 26, 2015, Centro Nacional de Investigaciones Oncologicas
From left to right are: Ana Ortega-Molina, Elena Lopez-Guadamillas and Manuel Serrano. Credit: CNIO

Researchers from the Spanish National Cancer Research Centre (CNIO) have shown that partial pharmacological inhibition of the PI3K enzyme in obese mice and monkeys reduces body weight and physiological manifestations of metabolic syndrome, specifically diabetes and hepatic steatosis (fatty liver disease), without any signs of side effects or toxicities. The work, published in the journal Cell Metabolism, is a collaborative project between the Tumor Suppression Group headed by Manuel Serrano at the CNIO (Madrid, Spain) and the Translational Gerontology Branch headed by Rafael de Cabo at the U.S. National Institute on Aging, National Institutes of Health (NIH, Baltimore, MD, USA), with participation of the NeurObesity group of CIMUS led by Miguel Lopez at the University of Santiago de Compostela (Santiago de Compostela, Spain).

The PI3K enzyme (phosphatidylinositol-3-kinase) regulates the balance between the production of biochemical cellular components (anabolism) and the use of nutrients (catabolism) that occurs in cells. Specifically, this enzyme promotes cellular anabolism, a process that can lead to the induction of growth and multiplication of cells, and ultimately could lead to cancer.

For this reason, scientists working in have been long pursuing pharmacological inhibitors of PIK3. This is the case of the CNIO, which has developed its own experimental inhibitor, CNIO-PI3Ki, currently being studied for applications in cancer treatment in combination with other compounds. As part of the characterization of the PI3K inhibitor and to understand how it affects the balance between the use and storage of nutrients in the body, the Serrano team decided to study the effects of CNIO-PI3Ki on metabolism.

"At this point we have veered away from the original anticancer aspects of these inhibitors. In our previous studies, we had seen that one of the normal physiological functions of the PI3K enzyme is to promote the storage of nutrients. We found this to be of particular interest because it is precisely this type of manipulation, regulation of the balance between storage and use of nutrients, that is sought after in treating obesity," explains Ana Ortega-Molina, the first author of the study, who is currently working at the Memorial Sloan-Kettering Cancer Center in New York.

Studies in mice and monkeys

To test the effect on metabolism, scientists working at the CNIO administered small doses of the CNIO-PI3Ki inhibitor during 5 months to who were fed a high-fat diet. During the first 50 days, the obese animals lost 20% of their body weight, at which point their weight stabilized. The treatment was administered for 5 months and during the whole time the maintained a stable weight (20% below the weight of non-treated obese mice), despite continuing feeding with a high-fat diet. They also improved their pathological symptoms of diabetes (high glucose levels in the blood) and hepatic steatosis (fatty liver).

"When it comes to obesity, constant weight loss can be extremely dangerous. The ideal solution is to alter the balance between the use and storage of nutrients, to strike a new balance in which there is greater use and less storage," explains Elena López-Guadamillas who, in collaboration with Ana Ortega-Molina, carried out most of the experimental work. This study showed that the drug had no side-effects and did not produce irreversible effects on metabolism, which is also desirable for its possible future use as a treatment in humans.

In non-obese animals that were fed a standard diet, the administration of the drug had no effect, which is another guarantee of safety. "This shows that the activity of the PI3K enzyme is only relevant when there is an excess of nutrients, that is, a high-calorie or high-fat diet," adds López-Guadamillas.

In collaboration with the U.S. National Institutes of Health (NIH), scientists from the CNIO tested the CNIO-PI3Ki compound on obese monkeys (macaques). To ensure higher safety margins, a very low dose was administered. Even so, the daily treatment of these obese animals over a 3-month period reduced the total amount of fatty tissue by 7.5% and improved the symptoms of diabetes.

Side-effects and safety

Obesity is one of the most important risk factors within the spectrum of serious diseases that constitute the metabolic syndrome. Many pharmacological agents have been discovered that lead to weight loss, but often with unacceptable toxic effects (partly due to the fact that these previous agents act on the brain centres that control appetite). In this respect, CNIO-PI3Ki seems to be the exception, at least in animal models thus far, as no such side-effects have been observed, even after long-term treatments (5 months in mice and 3 months in monkeys).

A series of safety characteristics that have been demonstrated in mice is shown below:

  • Selective: CNIO-PI3Ki only produces weight loss in mice that receive an excess of nutrients and not in mice that eat a normal balanced diet. This shows that PI3K plays an important role in the storage of nutrients when food intake is excessive, but is not so important under a normal diet.
  • Weight loss in the mice is due exclusively to loss of fatty tissue; no losses occur in other tissues such as liver, muscle or bone.
  • It does not affect the brain: CNIO-PI3Ki does not cross the blood-brain barrier.
  • It does not affect the hypothalamus: The hypothalamus is a specialized structure of the brain that is exceptional because it lacks a blood-brain barrier (a structure that controls the entrance of substances from the blood to the brain) and it controls many metabolic processes, including appetite and satiety. No effects on the main neuropeptides produced by the hypothalamus related to appetite and satiety have been noted in the mice. These last studies have been carried out in collaboration with the research group led by Miguel López at the University of Santiago de Compostela.
  • It works on a long-term basis: The effects of CNIO-PI3Ki were maintained over at least a 5-month period of treatment in mice, which suggests that resistance mechanisms are not developed. This is very important, as it is a common problem found in other compounds that affect metabolism.
  • Reversibility: The effects of CNIO-PI3Ki were reversible, which means that when the treatment was interrupted and a high-fat diet maintained, the mice regained weight. This indicates that CNIO-PI3Ki does not cause irreversible changes.

Future clinical trials in humans

The next logical step, once the beneficial effects of CNIO-PI3Ki have been demonstrated in obese mice and monkeys, is to perform clinical trials on humans. "The leap from animals to humans is complex, expensive and full of uncertainties. Many treatments that are promising in animals turn out not to be effective in humans or toxicities appear that were not observed in animals. But, obviously, in spite of the uncertainties, we have to give it a try," says Manuel Serrano. "Clinical trials require large investments and are undertaken with the aim of marketing a treatment. We are very optimistic about the possibility of entering into an agreement soon with a multinational pharmaceutical company interested in carrying out clinical trials with CNIO-PI3Ki to treat obesity and in humans," says Serrano.

Explore further: Scientists discover in studies with mice that an anti-cancer gene also fights obesity

Related Stories

Scientists discover in studies with mice that an anti-cancer gene also fights obesity

March 6, 2012
Researchers from the Spanish National Cancer Research Centre working with mice have revealed that one of the main genes protecting against cancer brings two additional health benefits by boosting longevity and combating obesity. ...

Study discovers new regulators of the most prevalent liver disease

January 7, 2014
Excessive alcohol consumption, as well as obesity leads to the accumulation of fat in the liver, a disease termed fatty liver disease (FLD) or steatosis. FLD is one of the most prevalent diseases in Western societies and ...

Experimental drug turns 'bad' white fat into 'good' brown-like fat

March 7, 2015
An experimental drug causes loss of weight and fat in mice, a new study has found. The study results will be presented Friday at the Endocrine Society's 97th annual meeting in San Diego.

Obesity and diabetes symptoms in mice improved by reversing brain inflammation

January 29, 2015
Using an antioxidant to reverse inflammation in the brain caused by a high-fat diet greatly improves symptoms related to obesity and type II diabetes, a new study from New Zealand's University of Otago suggests.

Special microbes make anti-obesity molecule in the gut

March 22, 2015
Microbes may just be the next diet craze. Researchers have programmed bacteria to generate a molecule that, through normal metabolism, becomes a hunger-suppressing lipid. Mice that drank water laced with the programmed bacteria ...

Researchers uncover more clues to how drug reverses obesity, diabetes, fatty liver disease

January 12, 2015
Researchers at the University of Michigan have identified how a promising drug in clinical trials for the treatment of obesity and related metabolic disorders improves the metabolism of sugar by generating a new signal between ...

Recommended for you

Large restaurant portions a global problem, study finds

December 12, 2018
A new multi-country study finds that large, high-calorie portion sizes in fast food and full service restaurants is not a problem unique to the United States. An international team of researchers found that 94 percent of ...

BMI is a good measure of health after all, new study finds

December 11, 2018
A new study from the University of Bristol supports body mass index (BMI) as a useful tool for assessing obesity and health.

A correlation between obesity and income has only developed in the past 30 years

December 11, 2018
It is well known that poorer Americans are more likely to be obese or suffer from diabetes; there is a strong negative correlation between household income and both obesity and diabetes. This negative correlation, however, ...

Simple tips to curb overindulgence can help stop pounds piling on at Christmas

December 10, 2018
A study by the University of Birmingham and Loughborough University has shown that regular weighing at home and simple tips to curb excess eating and drinking can prevent people from piling on the pounds at Christmas.

Obesity intervention needed before pregnancy

December 6, 2018
New research from the University of Adelaide's Robinson Research Institute supports the need for dietary and lifestyle interventions before overweight and obese women become pregnant.

Gene that lets you eat as much as you want holds promise against obesity

December 4, 2018
It sounds too good to be true, but a novel approach that might allow you to eat as much food as you want without gaining weight could be a reality in the near future.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.