*Purpose: Mitochondrial dysfunction in adipose tissue is one of the mechanisms contributing to obesity and its co-morbidities. Transfer of healthy mitochondria has proven successful in animal models and in clinical studies to protect against diseases attributed to mitochondrial dysfunction and oxidative stress. We hypothesize that treatment with healthy mitochondria may result in improved cellular oxidative capacity and better metabolic outcomes in mice on high fat diet.

*Methods: B6 male mice were fed HFD (60%kCal) starting at age of 6-wks until age of 18-wks. Mice were given single weekly injections of mitochondria isolated from donor mouse liver. Control mice received PBS injections. Molecular changes in gene expression were measured by RTPCR in various tissues including liver, and adipose depots. In vitro studies used 3T3-L1 and HepG2 cells and HEK293 as mitochondria donors and treated with mitochondria for 72 hrs.

*Results: In this study, we found that transplantation of healthy mitochondria in mice fed a high-fat diet have reduced body weights, adiposity and were protected from hepatic steatosis. Additionally, these mice showed increased energy expenditure, improved glucose tolerance and more insulin sensitivity. These physiological changes were accompanied by reduced expression of genes involved in lipid synthesis, inflammation, and increased expression of energy expenditure and fatty acid oxidation genes within the white adipose tissue. Adipocytes treated with mitochondria had 5-20-fold increase in the expression of energy expenditure genes (Ucp1, Pgc1α, Prdm16, Dio2) and proteins compared to vehicle treatment. Furthermore, mitochondria-treated adipocytes had an increase in cytokine (Il6, Tnfa, and Il10) production and we found that the metabolic benefits of mitochondrial treatment in adipocytes was partially dependent on IL6. Mitochondria treated adipocytes had significantly higher gene expression of fatty acid oxidation (Cpt2, Cpt1a, Cpt1b, Acox1, Hadha, Acadl,and Acadm) and autophagy (Atg3, p62, Ulk1, Beclin, Lc3b, Atg7, Atg9 and Lamp2) along with higher protein levels of LC3B. These effects were reproducible when cells were treated with high concentrations of free fatty acids. Consequently, mitochondria-treated adipocytes showed an increase in oxygen consumption, ATP production and lipolysis.

*Conclusions: Our findings demonstrate that mitochondrial transplantation is an alternative strategy of improving adipocyte function in obesity by restoring oxidative capacity, suppressing inflammation and lipid synthesis, allowing for reduced weight gain. Collectively, our study highlights the therapeutic potential of mitochondrial transplantation in promoting better metabolic outcomes in the treatment of diet-induced obesity.

« Back to 2022 American Transplant Congress