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May 24, 2016
Nanoparticles target, transform fat tissue
At a Glance
- Nanoparticles designed to target white fat and convert it to calorie-burning brown fat slowed weight gain in obese mice without affecting food intake.
- This proof-of-concept work could lead to new therapies to treat obesity.
More than 2 in 3 adults nationwide are considered overweight or obese. In recent years, researchers have gained insights into the roles of different types of fat tissue in weight control. Adults have mostly white fat, in which excess calories are stored as chemicals called fatty acids. Too much white fat increases the risk of several metabolic disorders.
Brown fat, in contrast, burns energy to create heat and help maintain body temperature. Infants have brown fat when they're born, but we lose it as we age. Brown fat was only recently proven to exist in adults. Since brown fat cells are able to burn calories, they could potentially play a role in strategies to reduce obesity and its associated disorders.
Fat tissue and its supporting blood vessel network can change over time. Compounds such as rosiglitazone (Rosi) and prostaglandin E2 analog (PGE2) have been shown to have “browning” effects on white fat tissue—increasing metabolism and the growth of new blood vessels. However, such drugs may have unwanted effects on other tissues.
Nanometer-sized particles, or nanoparticles, can be designed to target specific organs or tissues. The technology is current being explored in cancer and other therapies. A team led by Dr. Robert Langer at MIT and Dr. Omid Farokhzad at Brigham and Women’s Hospital designed nanoparticles to target browning agents to fat tissue. The study, funded in part by NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), appeared on May 17, 2016, in Proceedings of the National Academy of Sciences.
The researchers developed nanoparticles with a core containing Rosi or PGE2 along with a polymer called PLGA that enables slow release of the drug. To target the nanoparticles to fat tissue, the outer surface was made of a polymer called PEG attached to either iRGD or P3—compounds that bind to molecules inside the blood vessels of fat tissue. The particles were delivered to the mice by intravenous injection.
Compared to control mice given the drugs free in solution or in nontargeted nanoparticles, the mice treated with the targeted nanoparticles had darker white fat. Under the microscope, their fat cells appeared smaller and there were more blood vessels. Expression of UCP1, a marker of brown fat cells, was significantly raised by the targeted nanoparticles as well.
The researchers next tested the Rosi nanoparticles in obese mice fed a high-fat diet. The targeted nanoparticles inhibited body weight gain by about 10% compared to untreated mice, or to mice treated with Rosi in solution or in nontargeted nanoparticles. Mice treated with targeted nanoparticles had smaller fat cells, more blood vessels, and higher levels of brown fat markers. Notably, the groups had similar food intakes. These findings show that the targeted Rosi nanoparticles reduced weight gain by browning fat tissue.
This study focused on Rosi as a proof of concept. In the clinic, Rosi has serious side effects, but agents other than Rosi or PGE2 could be loaded into the nanoparticles. “The advantage here is now you have a way of targeting it to a particular area and not giving the body systemic effects,” Langer says. “You can get the positive effects that you’d want in terms of anti-obesity but not the negative ones that sometimes occur.”
—by Harrison Wein, Ph.D.
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References: Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles. Xue Y, Xu X, Zhang XQ, Farokhzad OC, Langer R. Proc Natl Acad Sci U S A. 2016 May 17;113(20):5552-7. doi: 10.1073/pnas.1603840113. Epub 2016 May 2. PMID: 27140638.
Funding: NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB) and National Cancer Institute (NCI); Koch–Prostate Cancer Foundation Award in Nanotherapeutics; and Swedish Research Council.