Nanoparticle-drug combo has potential to treat obesity and diabetes
In a potential breakthrough for the treatment of obesity and diabetes, Purdue University scientists have found a way to deliver a drug directly to stored white fat cells to turn them into more easily burned brown fat cells.
Credit: Alexander M. Gokan
White adipose tissue, most associated with obesity, is a type of fat that collects in the body for long-term storage of energy. It's possible humans evolved to store white fat to act as insulation and energy storage. However, as we have become over-fed and less active, we have less need for the energy stored in white fat and it over-accumulates, leading to metabolic diseases such as diabetes and obesity. More than one-third of Americans are obese today, and nearly 10% have diabetes, according to the Centers for Disease Control and Prevention.
Brown fat is more readily burned by the body, dissipating energy into heat. Scientists at Purdue University (Indiana, USA) have been looking for ways to decrease white fat in favour of brown fat, through a signalling pathway that is known to regulate cell differentiation and cell identity.
In so-called Notch signalling, a cell sends a signal to a neighbouring cell to control that neighbour's gene transcription and identity. Disrupting that signal in a progenitor cell destined to become one of the undesirable white fat cells leads to the creation of brown fat.
Meng Deng, an Assistant Professor in Agricultural and Biological Engineering, and colleague Shihuan Kuang, Professor of Animal Sciences, describe their latest research in the journal Molecular Therapy. They have, for the first time, used an engineered polymeric nanoparticle for controlled delivery of a Notch-signalling inhibitor directly to white fat cells. In a mouse model, the nanoparticle – made of an FDA-approved polymer known as PLGA and containing the drug Dibenzazepine – disrupted Notch signalling and led to the creation of brown fat cells.
"We can control the delivery to specific sites in the body, in this case the bad fat or white fat cells," Deng said. "Once those engineered particles are inside the fat cells, they can slowly release the drug in the cells, potentially limiting the off-target interactions in other tissues and reducing the frequency of dosing."
The particles, which are less than 200 nanometres in size, are readily taken up by the fat cells through a process called endocytotic trafficking and subsequently undergo a rapid endo-lysosome escape to the cytosol within the cell membrane.
"The particle was actually picked up by the cell. It's like it's being eaten by the cells," Kuang said. "This limits the particle from going anywhere else."
Since the nanoparticles containing the drug are injected into fat, Deng said it may be possible to develop therapies that target fat loss in specific parts of the human body. In the mouse model, targeting a specific fat depot with weekly injections of nanoparticles is sufficient to bring about systemic improvements in glucose tolerance and insulin sensitivity. Being overweight is also a factor in developing type 2 diabetes. Removing excess fat would likely decrease the odds of developing the disease.
Deng has filed a patent for the process and has created a startup, Adipo Therapeutics LLC, to continue testing and eventually commercialising the technology for use in humans.