Obesity and overweight are already one of the major health challenges for society as a whole, causing serious symptoms including diabetes and cardiovascular disease, and have become the second leading preventable death. The direct cause of obesity is the expansion of white adipose tissue (WAT), which in turn is caused by the formation and growth of fat cells. In the body, fat cells can function by storing lipids in the form of triglycerides (TG).
Cationic nanomaterials, represented by polyamide-amine (PAMAM) dendrimers, have shown great potential in the treatment of various inflammatory diseases and cancers by neutralizing negatively charged pathogens, yet such materials have never been applied to obesity. During the development of obesity, the expansion of WAT is accompanied by an increase in the extracellular matrix (ECM), which contains glycosaminoglycans, the most negatively charged biological macromolecules known. The anion properties of ECM in adipose tissue indicate that cationic nanomaterials are expected to achieve good enrichment behavior in this kind of tissue.
Among these PAMams, P-G3 is a third-generation PAMAM dendrimer with 32 surface amine groups. Using P-G3, Professor Jun Qiang and Professor Jinrong Liang of Columbia University and others developed a polycation-based nanomedical. The nanomedicine can selectively target visceral fat during intraperitoneal delivery due to its high charge density. In addition, P-G3 treatment of obese mice inhibited visceral obesity, increased energy expenditure, prevented obesity, and alleviated related metabolic dysfunction. In vitro adipogenesis models and single-cell RNA sequencing showed that P-G3 separated adipocyte lipid synthesis and storage from adipocyte development, at least by synergically regulating nutrient sensing signaling pathways, to produce adipocytes with normal function but lacking hypertrophic growth. This study focuses on visceral obesity, develops targeted therapeutic strategies based on cationic nanomaterials, and illustrates the potential of such materials in the treatment of metabolic diseases. The work is published in Nature Nanotechnology under the title "Selective targeting of visceral adiposity by polycation nanomedicine."
First, P-G3 can be selectively distributed in visceral fat
The study first found that P-G3 can use the high anionic ECM in adipose tissue to bind to adipose tissue. ECM isolated from visceral epididymal white adipose tissue (eWAT) and subcutaneous inguinal white adipose tissue showed strong uptake of Cy5 fluorescically labeled P-G3. In addition, in vitro incubation of P-G3 with intact organs showed that the fluorescence signal in iWAT and eWAT was much stronger than in non-adipose tissue. These data indicate that P-G3 has a preferential biological distribution in WAT (Figure 1).
2. P-G3 inhibits obesity
Indirect calorimetric analysis showed that P-G3 treatment increased caloric production and oxygen consumption without affecting motor activity, respiratory exchange rate and food intake. In addition, obesity-related metabolic dysfunction, especially glucose intolerance and insulin resistance, was also alleviated. Cell experiments showed that although P-G3 could accelerate the development of fat cells, it also inhibited the growth of hypertrophy cells. Notably, P-G3 treatment primarily inhibited lipid synthesis genes without affecting pan-adipocyte markers in eWAT, implying that downregulation of adipocyte genes is a secondary factor in alleviating lipid storage in chronic therapy. Mechanism studies have shown that P-G3 functions through a synergistic mechanism, possibly involving inhibited NAD and mTOR signaling, to separate adipogenesis from adipogenesis (Figure 2).
P-G3 nanoparticles improve the targeting of visceral fat
To further improve the visceral fat distribution of P-G3 and reduce the risk of off-target in other tissues, the authors covalently attached lipophilic chains of five cholesterol molecules to P-G3. The resulting P-G3-Chol (5) can self-assemble in water to form spherical nanoparticles and maintain a cationic surface. P-g3-chol (5) nanoparticles showed the same adipocyte entosis uptake pattern as unmodified P-G3 and could similarly promote adipogenesis. What's more, the nanoparticles showed similar or slightly higher visceral fat reservoir distribution than P-G3, but their distribution in the liver, kidneys, and lungs was significantly lower. In vivo experiments, mice treated with nanoparticles showed better glucose tolerance. Similarly, the mTOR signaling pathway in nanoparticle treated eWAT was significantly inhibited. In summary, P-G3-Chol (5) nanoparticles show great therapeutic potential in treating visceral obesity in diet-induced obesity mouse models (Figure 3).
【 Conclusion 】
The authors conclude that cationic charge is related to the efficacy of polycations, but also produces corresponding toxicity. This study shows that modifying P-G3 with cholesterol can hopefully find the optimal balance between efficacy and safety. In addition, using the carrier capacity of polycations and visceral fat specific targeting properties, it is expected that fat manipulators can be encapsulated into P-G3 nanomaterials to deliver them specifically to visceral fat for additional anti-obesity benefits, while also reducing off-target effects. Together, the study highlights a strategy to target visceral obesity and explores the therapeutic applications of cationic nanomaterials in metabolic diseases.
