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Drug Delivery

Drug Delivery - Poster Session C

Poster J7 - Modulation of Autophagy and Mitophagy in Adipocytes and Adipose Stem Cells using a Drug Delivery System

Friday, October 25, 2024
10:00 AM – 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  The proper functioning of white and brown adipose tissues is essential for regulating nutrient balance and maintaining metabolic health. Adipocytes in white adipose tissue (WAT) store fatty acids and glucose as triglycerides, while those in brown adipose tissue (BAT) oxidize lipids and glucose to produce body heat (thermogenesis). WAT also contains beige adipocytes that share this thermogenic role. Autophagy is the process in which the cell breaks down and destroys old or damaged proteins and substances within the cell and uses what's broken down as a recycling mechanism for important cell functions. Also, autophagy is crucial for preserving mitochondrial health in cells by eliminating old or damaged mitochondria (mitophagy). Autophagy plays a role in several processes impacted during WAT maladaptation, such as adipogenesis, adipocyte and macrophage function, inflammatory response, and fibrosis. Dysregulation of WAT autophagy is associated with obesity and diabetes. Nevertheless, the current role of autophagy physiologically in mature WAT and BAT is unclear and still being studied. Importantly, there are not therapy options to modulate autophagy in mature adipocytes. The purpose of this study is to explore the use of Lanthionine Ketamine (LK), a metabolite that increase autophagy in motor neuron cells, and misoprostol, a drug known to decrease mitophagy using a local drug delivery strategy.

Materials and

Methods:  For the drug delivery system, we used lipid coated mesoporous silica nanoparticles (aka protocells). Mesoporous silica nanoparticles (MSNPs) were synthesized using a solution-based surfactant directed self-assembly method. Liposomes were fused to MSNPs through electrostatic interactions. Human adipose derived stem cells (hASC) were differentiated to mature adipocytes. To assess protocell uptake, fluorescently labeled protocells were used to treat hASC and mature adipocytes. After treatment, a fluorescent plate reader was used to measure florescence in the cells. hASC and mature adipocytes were treated either with LK, or misoprostol alone or loaded in protocells. Different concentrations of LK and misoprostol were used. Autophagy changes were measured with gene markers of LC3B and Beclin1 quantified using RT-PCR. Western blot of LC3 was used to measure protein expression of autophagy. To evaluate changes in mitophagy of cells treated with misoprostol, we evaluated changes of BNIP3 gene levels using RT-PCR; and protein levels using immunohistochemistry.

Results, Conclusions, and Discussions: Protocells were successfully synthetized and taken up by hASC and mature adipocytes as observed with the fluorescent plate reader results. Negatively charged protocells had more uptake compared to neutral and positively charged protocells. Misoprostol treatment significant decreased the gene levels of BNIP3/L and these results were confirmed by immunohistochemistry were the intensity of BNIP3 was reduced compared to untreated cells. hASC and mature adipocytes were treated with LK and no toxic effects were observed. In pending current studies, the gene expression of Beclin and LC3B as well as the protein expression of LC3 are being evaluated of hASC and adipocytes treated with LK. This data suggests that we can use a drug delivery system to adipocytes and hASC to modulate autophagy and mitophagy. Future studies will evaluate the implication of this autophagy and mitophagy modulation in functional effects such as lipolysis, glucose uptake, thermogenic activity.

Acknowledgements (Optional):  National Institute of Health ESTEEMED Grant at the University of Texas at San Antonio 5-R25-EB027605-05