Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term.

Introduction: Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. Methods: We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Results: Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Discussion: Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

Role of Exosomes Derived from Adipose Tissue under Obese Conditions in Skeletal Muscle and Liver Cells: Commonalities and Differences.

SCOPE: To determine the correlation between obesity and insulin resistance in skeletal muscle and liver tissues, this study isolates exosomes from adipose tissue under obese conditions and investigates the effect of adipose tissue-derived exosomes (Ad-exosomes) in mouse muscle (C2C12 cells) and liver cell lines (AML12 cells). METHODS AND RESULTS: The study isolates exosomes from the adipose tissue of normal diet-fed mice or high-fat diet (HFD)-fed obese mice and confirms the uptake into differentiated C2C12 and AML12 cells. Ad-exosomes from HFD-fed mice induce insulin resistance, triglyceride (TG) accumulation, endoplasmic reticulum stress, and inflammation in both C2C12 and AML12 cells. Interestingly, the study finds that the TG accumulation induces by Ad-exosomes from HFD-fed obese mice is dramatically increased in AML12 cells compared with that in the differentiated C2C12 cells, and glucose uptake following the same treatment is decreased in C2C12 cells and increased in AML12 cells. In addition, Ad-exosomes from HFD-fed obese mice cause not only TG accumulation but also lipogenesis in AML12 cells. CONCLUSIONS: The results suggest that Ad-exosomes from HFD-fed obese mice cause insulin resistance in both the muscles and liver, but their effects on metabolism during the development of insulin resistance vary between tissues.