Fat under attack – nanoparticles tackle obesity

According to the World Health Organization, around 40% of all adults are overweight, and around a third of those are obese. Alarmingly, overweight/ obesity is the fifth leading cause of death and considerably increases the risk of getting other diseases, such as diabetes. Unfortunately, curing obesity is not that simple. Since it is a multifactorial disease, lifestyle interventions including exercise and diet are not always sufficient to achieve weight loss. Hence, there is a high interest in the development of safe anti-obesity drugs. In 2009, brown adipose tissue emerged as attractive drug target and the application of targeted nanoparticles could be a novel solution to deliver drugs selectively into adipose tissue in order to avoid side effects.

Brown fat: burning calories while you rest!

As early as the 1980s, the principle of activating brown adipose tissue (BAT) to raise energy expenditure without exercising gained interest as a strategy to slow weight gain. BAT is able to produce heat and increase body temperature when ambient temperature is too low. In contrast to white adipose tissue (WAT), which stores energy as fat, BAT burns calories for heat generation. Although it was proven to efficiently impact energy balance in rodents, BAT was overlooked as a relevant drug target in adult humans until recently. Two breakthrough discoveries in the last decade revived this area of research: First, the presence of BAT in humans and its responsiveness to a low ambient temperature has been shown in different independent studies using advanced imaging technologies. Second, it has been shown that adipose tissue is highly plastic and “bad” WAT can be transformed to thermogenically active calorie consuming “good” BAT-like fat in response to certain triggers.

Destination fat

The application of specific nanoparticles as a vehicle might overcome the challenge of targeted drug delivery. In principle, polymeric nanoparticles can be loaded with the drug of interest. In order to guide the drug-loaded nanoparticle to the site of interest, specific peptides are inserted in the nanoparticles’ coat acting as external signal.

Using this approach, the research team of Langer and Farokhzad was able to deliver factors inducing brown-like fat cells specifically to adipose tissue. In this study recently published in PNAS, nanoparticles were either loaded with rosiglitazone or PGE2. Two peptides recognizing antigens in the vasculature of adipose tissue were conjugated to the surface of the nanoparticles for targeted delivery. The suitability of these nanoparticles as a vehicle was proven in their first experiment: Injection of peptide-conjugated, rosiglitazone-loaded nanoparticles into lean mice led to their accumulation in WAT depots and a transformation of white to brown-like fat was observed 15 days later. In a second approach aiming to test if this induction of brown-like fat has a significant impact on energy metabolism, constructs were injected into mice under high-fat diet. In this obesogenic setting, mice injected with the targeted rosiglitazone-loaded nanoparticles gained significantly less weight compared to untreated mice. Remarkably, food intake was equal in the different groups.

This study highlights that the usage of targeted nanoparticles might be a promising approach facilitating the development and authorization of anti-obesity drugs with fewer side effects. Meanwhile, we can already start changing the central root of this global health burden – and start a healthy life style.

Dr. Manuela Fleckenstein-Elsen

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References

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• Bonet ML et al. Biochim Biophys Acta 2013;1831(5):969–985.
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• Xue Y et al. Proc Natl Acad Sci USA 2016;113(20):5552–5557.

• http://www.who.int/mediacentre/factsheets/fs311/en/
• http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm143349.htm