The nanoparticle converts unhealthy fat into healthier fat cells.

A new nanoparticle remodels fat into ‘dwarf cells’ and stops more fat from developing. The nanoscale fat buster also treated obesity in mice and inhibited ‘fat-forming’ genes.

Resculpting fat

Often seen as a cumbersome ballast that spoils the line of our beachwear, fat cells have had a bad rap in the past. However, these squishy balls of lipids are crucial for the everyday running of our bodies – storing essential nutrients to draw on when needed (or not, depending on your waist size). This versatile substance also insulates the nerve cells that make up the intricate signaling system throughout our bodies; it can even stop us from freezing.

However, this cellular reserve can go awry when it stores too much fat leading to numerous metabolic diseases such as diabetes, obesity, or hypertension (high blood pressure). To further add to the mire, unhealthy fat stores are notoriously difficult to treat as all this tissue exists as deposits around the body. And even harder to treat is the ‘hidden or visceral fat’ surrounding the abdominal organs deep within the body.

Now, researchers from Columbia University say they have developed a charged nanoparticle that is attracted to these ‘depots,’ stopping the fat cells or adipocytes from expanding any further by turning them into ‘healthy fat.’

The particle, dubbed PG-3, is a cation meaning its positively charged. The team says this ionic facet also means it’s attracted to the negatively charged extracellular matrix supporting the adipocytes, known collectively as adipose tissue. Once injected into obese mice, the nanoparticle was even able to locate and treat visceral fat, responsible for belly fat, and deemed virtually untreatable until the study.

 Li Qiang, associate professor of cell biology and pathology at Columbia, states, “Our approach is unique — It departs from the pharmacological or surgical approaches.” He says, “We used cationic charge to rejuvenate healthy fat cells, a technique no one has ever used to treat obesity. I think this novel strategy will open the door to healthier and safer reduction of fat.”

Good fat, bad fat

 Adipocytes are fascinating entities whose sole purpose is to store lipids. During this function, which involves the activation of genes for lipid synthesis, the size of a fat cell can grow up to 20 times its original diameter.

Theoretically, this expansion could increase the number of lipids stored by 8,000 times as compared to the capacity of the original healthy or ‘dwarf’ fat cell. Accordingly, even approaching these gross proportions, inflammation and a whole host of metabolic conditions usually ensue.

Therefore, uncoupling this unhealthy excess production of lipids from healthy fat metabolism, where these triglycerides are being synthesized and degraded in a balanced manner, could hypothetically treat metabolic diseases. The team aims to achieve this one day using their new nanoparticle, PG-3.

Potential obesity treatment

Going towards this, the first thing they investigated in their study was the mode of action of their particle. When injected into obese mice, the PG-3 quickly spread throughout the visceral adipose tissue to resculpt it and inhibit further expansion without damaging it. Ultimately, they say, the treatment produces healthy fat cells, causing the mice to lose weight, essentially treating their obesity.

In their paper, the scientists explain that past studies have linked visceral fat to far more severe health issues than subcutaneous fat, which lies just under the skin. And say, “A major challenge in obesity treatment is that fat tissue is not continuous in the body but is found in bits as depots, which has made pinpointing at the exact location difficult.”

They write that the results are exciting because “Unlike subcutaneous fat with multiple available approaches, the only treatment options for visceral adiposity is highly risky surgical removal developed in rodents and baboons.”

“We’re very excited to discover that cationic charge is the secret to targeting adipose tissue,” says Qiang. “Now we can shrink fat in a depot-specific manner — anywhere we want — and in a safe way without destroying fat cells. This is a major advance in treating obesity.”

Creating the nanoparticle

The group describes PG-3 as comprised of polyamidoamine: a highly branched and ordered polymer called a dendrimer, known for self-assembling into particles containing multiple cavities for cargo. Cholesterol was then attached to get this particular dendrimer to organize itself into a nanoparticle to form PG-3 – a lipophilic molecule that dissolves in fat. Thus, the positive charge and lipophilicity make it highly attracted to negatively charged adipose tissue, where it can quickly disseminate.

They confirmed this by fluorescently tagging their particle to see precisely where it was going once injected into the obese mice. Using this method, they were also able to gain a firm handle on just how targeted and potentially safe the particle was. The team also conducted the same tests in healthy control mice.

Using dissection, the scientists found large amounts of fluorescently tagged PG-3 in white adipose tissue (unhealthy fat) compared to the low levels present in the attached organs and healthy brown fat deposits – suggesting their therapeutic is highly targeted and unlikely to travel to other tissues in the body.

Altering metabolism

The team observed that the PG-3 mice showed comparable glucose, insulin, and triglyceride levels with the control mice. They say this is because their nano-platform regulates lipogenesis genes to stop them from expressing–meaning that no more excess lipids can form while PG-3 is present in the adipose tissue.

And it doesn’t stop there. The scientists also noted that the nanoparticle has other great benefits, such as repressing genes to improve liver metabolism and alleviating obesity-associated metabolic dysfunctions, such as glucose intolerance and insulin resistance. Overall, PG-3 significantly improved the metabolic dysfunction associated with obesity in obese mice resulting in a 15 percent decrease in body weight and a 45 % reduction in fat mass.

Furthermore, there’s evidence that the nanoparticle may influence the fat-brain axis due to the fact it keeps MTOR activity at normal levels. Hyperactivity of this pathway, which is a key regulator of metabolism and the overall function of the body, has been linked to obesity and type 2 diabetes when it becomes disrupted. If this is the case, and PG-3 is helping to ‘reboot’ this pathway, it could also make the body expend more energy–burning more fat.

What it means

Professor Kam Leong, a leader in therapeutic cations at Columbia, explains, “With P-G3, fat cells can still be fat cells, but they can’t grow up. Our studies highlight an unexpected strategy to treat visceral adiposity and suggest a new direction of exploring cationic nanomaterials for treating metabolic diseases.”

However, the scientists make it clear that, at this stage, investigating the distribution and effect of PG-3 throughout adipose tissue is the main priority, with their therapeutic showing great potential to treat metabolic obesity.

The group concludes, “Collectively, our study highlights a strategy to target visceral adiposity and suggests cationic nanomaterials could be exploited for treating metabolic diseases.”