ABSTRACT
High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.
Subject(s)
Diet, High-Fat , Exosomes/metabolism , Insulin Resistance/genetics , Phosphatidylcholines/metabolism , Up-Regulation/genetics , Adipose Tissue/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Dyslipidemias/complications , Dyslipidemias/genetics , Dyslipidemias/pathology , Epithelial Cells/metabolism , Fatty Liver/complications , Fatty Liver/genetics , Fatty Liver/pathology , Feces , Gene Expression Regulation , Glucose Intolerance , Green Fluorescent Proteins/metabolism , Humans , Insulin/metabolism , Interleukin-6/blood , Intestines/cytology , Lipids/chemistry , Liver/metabolism , Liver/pathology , Macrophage Activation , Mice, Inbred C57BL , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction , Tetraspanin 30/metabolism , Tumor Necrosis Factor-alpha/bloodABSTRACT
OBJECTIVE: To determine whether the Bayes classifier can be used to distinguish between an ectopic and intrauterine pregnancy following embryo transfer based on early human chorionic gonadotropin (hCG) levels. STUDY DESIGN: Retrospective chart review of patients undergoing in vitro fertilization and diagnosed with a singleton intrauterine or with an ectopic pregnancy. Blood was drawn for hCG levels between days 12 and 20 after transvaginal oocyte aspiration. Statistical analysis was performed using a mixed effects model and the Bayes classifier. RESULTS: Singleton intrauterine (n=91) and ectopic gestations (n=14) were analyzed. hCG levels increased by 51% daily in both groups, but levels in ectopic pregnancies were only 14% of those from the control group on the same day (p<1×10-15). Using the Bayes classifier, an hCG value <18 IU/L indicated a large probability (>75%) that the pregnancy was ectopic. There was no statistically significant difference in regards to endometrial thickness (p=0.77), fresh or frozen embryo transfer (p=0.53), number of embryos transferred (p=0.13), donor or autologous oocytes (p=0.76), or the day of hCG draw (p=0.13 and 0.43 for first and second measurement). CONCLUSION: The Bayes classifier can be used as a tool to alert the healthcare provider of a possible ectopic gestation.
Subject(s)
Bayes Theorem , Chorionic Gonadotropin , Embryo Transfer , Pregnancy, Ectopic , Chorionic Gonadotropin/blood , Female , Fertilization in Vitro , Humans , Pregnancy , Retrospective Studies , Risk AssessmentABSTRACT
Endometrial dysfunction affects approximately 1% of infertile women, and there is currently no standard therapy for improving fertility treatment outcomes in these patients. In our study, we utilized a rodent model of thin endometrium to test whether intrauterine application of adipose-derived stromal vascular fraction cells (SVF) could improve morphological and physiological markers of endometrial receptivity. Using anhydrous ethanol, endometrial area and gland density were significantly reduced in our model of thin endometrium. Application of SVF was associated with a 29% reduction in endometrial vascular endothelial growth factor (VEGF) expression and significant increases in uterine artery systolic/diastolic velocity ratios and resistance index values, suggesting reduced diastolic microvascular tone. However, no significant improvements in endometrial area or gland density were observed following SVF treatment. 3D confocal imaging demonstrated poor engraftment of SVF cells into recipient tissue, which likely contributed to the negative results of this study. We suspect modified treatment protocols utilizing adjuvant estrogen and/or tail vein cell delivery may improve SVF retention and therapeutic response in subsequent studies. SVF is an easily-obtainable cell product with regenerative capability that may have a future role in the treatment of infertile women with endometrial dysfunction.
Subject(s)
Adipose Tissue/cytology , Endometrium/cytology , Stromal Cells/cytology , Adipocytes/cytology , Adipocytes/metabolism , Adipose Tissue/metabolism , Adiposity/physiology , Adult Stem Cells/cytology , Animals , Cells, Cultured , Endometrium/metabolism , Female , Infertility, Female/pathology , Infertility, Female/therapy , Models, Animal , Rats , Rats, Sprague-Dawley , Stromal Cells/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVE: To report a live birth after in vitro maturation (IVM) of oocytes retrieved from extracorporeal ovarian tissue aspiration in the setting of fertility preservation. DESIGN: Observational study. SETTING: Academic center. PATIENT(S): A 23-year-old woman. INTERVENTION(S): IVM from extracorporeal ovarian tissue aspiration. MAIN OUTCOME MEASURE(S): Live birth after IVM. RESULT(S): A 23-year-old woman conceived with embryos derived from extracorporeal oocyte aspiration followed by IVM, embryo freezing, and frozen embryo transfer. CONCLUSION(S): A healthy live birth from extracorporeal aspiration of immature oocytes, IVM, and a frozen embryo transfer after 5 years was documented. Consideration of this technique should be made as a primary or adjunct intervention in the setting of fertility preservation.
