Western-style diet in the presence of elevated circulating testosterone induces adipocyte hypertrophy without proinflammatory responses in rhesus macaques.

PROBLEM: Anovulatory infertility is commonly associated with hyperandrogenemia (elevated testosterone, T), insulin resistance, obesity, and white adipose tissue (WAT) dysfunction associated with adipocyte hypertrophy. However, whether hyperandrogenemia and adipocyte hypertrophy per se induce a proinflammatory response is unknown. METHOD OF STUDY: Young adult female rhesus macaques were exposed to an obesogenic Western-style diet (WSD) in the presence of elevated circulating testosterone (T+WSD) or a low-fat control diet with no exogenous T. Immune cells residing in visceral omental white adipose tissue (OM-WAT), corpus luteum and the contralateral ovary, endometrium, lymph nodes, bone marrow, and peripheral blood mononuclear cells were characterized by flow cytometry during the luteal phase of the reproductive cycle. RESULTS: Following one year of treatment, T+WSD animals became more insulin-resistant and exhibited increased body fat and adipocyte hypertrophy compared to controls. T+WSD treatment did not induce macrophage polarization toward a proinflammatory phenotype in the tissues examined. Additionally, T+WSD treatment did not affect TNFα production by bone marrow macrophages in response to toll-like receptor agonists. While the major lymphoid subsets were not significantly affected by T+WSD treatment, we observed a significant reduction in the frequency of effector memory CD8+ T-cells (Tem) in OM-WAT, but not in other tissues. Notably, OM-WAT Tem frequencies were negatively correlated with insulin resistance as assessed by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). CONCLUSION: This study shows that short-term T+WSD treatment induces weight gain, insulin resistance, and adipocyte hypertrophy, but does not have a significant effect on systemic and tissue-resident proinflammatory markers, suggesting that adipocyte hypertrophy and mild hyperandrogenemia alone are not sufficient to induce a proinflammatory response.

Functional evaluation of the cystic fibrosis transmembrane conductance regulator in the endocervix†.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane chloride/bicarbonate ion channel in epithelial cells. Mutations in CFTR cause cystic fibrosis, a disease characterized by thickened mucus secretions and is associated with subfertility and infertility. CFTR function has been well characterized in vitro and in vivo in airway and other epithelia studies. However, little is known about CFTR function in the cervix in health and its contribution to cyclic regulation of fertility from endocervical mucus changes. Contributing to this research gap is the lack of information on the effect of sex steroid hormones on CFTR expression in cervical epithelial cells across the menstrual cycle. Herein, we demonstrate the hormonal regulation of CFTR expression in endocervical cells both in vitro and in vivo, and that conditionally reprogrammed endocervical epithelial cells can be used to interrogate CFTR ion channel function. CFTR activity was demonstrated in vitro using electrophysiological methods and functionally inhibited by the CFTR-specific inhibitors inh-172 and GlyH-101. We also report that CFTR expression is increased by estradiol in the macaque cervix both in vitro and in vivo in Rhesus macaques treated with artificial menstrual cycles. Estrogen upregulation of CFTR is blocked in vivo by cotreatment with progesterone. Our findings provide the most comprehensive evidence to date that steroid hormones drive changes in CFTR expression. These data are integral to understanding the role of CFTR as a fertility regulator in the endocervix.

Targeted Nanoparticles with High Heating Efficiency for the Treatment of Endometriosis with Systemically Delivered Magnetic Hyperthermia.

Endometriosis is a devastating disease in which endometrial-like tissue forms lesions outside the uterus. It causes infertility and severe pelvic pain in ≈176 million women worldwide, and there is currently no cure for this disease. Magnetic hyperthermia could potentially eliminate widespread endometriotic lesions but has not previously been considered for treatment because conventional magnetic nanoparticles have relatively low heating efficiency and can only provide ablation temperatures (>46 °C) following direct intralesional injection. This study is the first to describe nanoparticles that enable systemically delivered magnetic hyperthermia for endometriosis treatment. When subjected to an alternating magnetic field (AMF), these hexagonal iron-oxide nanoparticles exhibit extraordinary heating efficiency that is 6.4× greater than their spherical counterparts. Modifying nanoparticles with a peptide targeted to vascular endothelial growth factor receptor 2 (VEGFR-2) enhances their endometriosis specificity. Studies in mice bearing transplants of macaque endometriotic tissue reveal that, following intravenous injection at a low dose (3 mg per kg), these nanoparticles efficiently accumulate in endometriotic lesions, selectively elevate intralesional temperature above 50 °C upon exposure to external AMF, and completely eradicate them with a single treatment. These nanoparticles also demonstrate promising potential as magnetic resonance imaging (MRI) contrast agents for precise detection of endometriotic tissue before AMF application.