Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles

Abstract

The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases.

Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function

“…Notably, implantation of beige adipocytes in HFD‐fed mice improved glucose tolerance, reduced liver steatosis and normalized adiponectin levels (Min et al ., ). Furthermore, angiogenesis‐targeted nanoparticles (atNP) prevented obesity in mice by promoting the transformation from white to beige adipocytes (Xue et al ., ), suggesting that previous angiogenesis is required for the ‘beigeing’ processes (De Matteis et al ., ; Frontini et al ., ; Disanzo and You, ). Based on this information, atNPs could be used to target dysfunctional PVAT.…”

Drug Delivery Strategies for the Treatment of Metabolic Diseases

“…Recently, a targeted strategy was utilized to treat obesity in our group . Angiogenesis, playing a major role in the expansion and regression of adipose tissue, makes the vasculature a potential therapeutic target for obesity and related metabolic diseases 5a,33,34.…”

“…Recently, a targeted strategy was utilized to treat obesity in our group . Angiogenesis, playing a major role in the expansion and regression of adipose tissue, makes the vasculature a potential therapeutic target for obesity and related metabolic diseases 5a,33,34. Stimulation of angiogenesis results in transforming adipose tissue from energy storage status into energy expenditure status, which is expected for obesity treatment .…”

Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets

“…Nanotechnology has now emerged as a novel scientific field utilizing a variety of nanoparticles to offer targeted drug delivery options (Psarros et al , ), and as such it could allow for direct targeting of PVAT. Indeed, peptide‐conjugated nanoparticles have recently been revealed as a successful means of specifically targeting AT (Xue et al , ). Although it is unclear whether similar methods could be applied specifically to PVAT, they certainly appear as promising potential tools for efficient and specific therapeutic interventions.…”