Gold nanoparticles to ameliorate obesity related glucose intolerance
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Obesity is associated with a number of metabolic disorders such as insulin resistance, glucose intolerance, and dyslipidaemia. The main objective of this research work focused on potential therapeutic applications of “naked” gold nanoparticles (AuNPs) in the treatment of obesity-related metabolic diseases. In this thesis, 21 nm spherical citrate-coated, unmodified also known as “naked” AuNPs were studied and assessed using both in vitro cell and in vivo animal studies. We observed an increased rate of “naked” AuNPs cellular uptake non-selectively and non-specific accumulation in all cell types studied compared to surface modified AuNPs. Macrophages in adipose tissue played a crucial role contributing to the low-grade chronic inflammation present in obesity and pathogenesis of obesity-related metabolic disorders. Our in vitro studies also showed that AuNPs can act on the complex adipocyte-macrophage interaction altering the adipocytes lipid and fatty acid metabolic markers in a macrophage-dependent manner. Based on this unique finding, we further investigated the long-term safety of AuNP treatment and their effect on adipose tissue macrophages using in vivo mice model with dietary obesity. In this study, 7 week old male C57Bl/6 mice were fed a high fat diet (HFD) and received daily intraperitoneal injection of AuNPs (0.785 μg or 7.85 μg/g/day) for 9 weeks. Our results showed that the AuNP-treated mice with dietary obesity showed significantly improved body morphometry measurement with significantly reduced blood lipid levels and prevented the development of glucose intolerance. We proposed that the alterations in the local pro-inflammatory cytokine environment due to modification of macrophage activity by AuNPs may be the key underlying mechanism for the weight loss observed in the HFD-fed mice. In addition, there was no indication of liver toxicity after 9 weeks of daily AuNPs exposure. Following that, male C57Bl/6 mice (7 week old) feeding a 10 week HFD were used as an in vivo obese model with chronic obesity and metabolic disorder to study the effect of short-term AuNP treatment. At week 10, the obese mice were continued on a HFD and AuNP treatment (0.0785 μg, 0.785 μg, or 7.85 μg/g/day) administered daily via intraperitoneal injection for an additional 5 weeks. Our findings showed that the 5 weeks AuNP-treated obese mice had little to no impact on body morphometric measurements of mice with existing obesity. However, all obese mice treated with 5 weeks of AuNPs showed amelioration of glucose intolerance. Our results also showed altered the inflammatory cytokines, lipid, and glucose marker expression in the liver. Our findings suggest that obese mice treated with AuNPs could have a lower the risk of developing obesity-related complications such as glucose intolerance and liver steatosis. This research work demonstrated the anti-obesity and anti-diabetic properties of AuNPs which has led to our proposal that AuNPs can serve as a novel therapeutic treatment strategy in the prevention of obesity and obesity-related metabolic disorders.
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