Apelin-APJ signaling in mediating the beneficial effects of maternal exercise on placenta and fetal intestinal development

Obesity has reached epidemic proportions in the U.S. and worldwide. Importantly, an overwhelming body of data supports the inheritable link between maternal obesity (MO) and offspring metabolic dysfunctions. Maternal Exercise (ME), on the other hand, has a preventative effect by improving the metabolic capacity of offspring. However, the underlying mechanisms remain to be defined. The placenta, meanwhile, is one of the key organs mediating nutrient and oxygen delivering to the fetus, so for the intestine, which is critical for nutrient absorption after birth. We hypothesized that ME improves the development of placenta and fetal intestine impaired by MO. We found that the placental vascularization/angiogenesis and nutrient transport activities impaired by MO was prevented by exercise during pregnancy. Notably, apelin, a hormone known to stimulate angiogenesis, was downregulated by MO but remarkably recovered by ME. Similarly, we found that ME improved fetal intestinal development, which had been compromised by MO. The villus length and epithelial proliferation markers were decreased due to MO, but recovered by ME. Consistently, ME also facilitated oxidative metabolism in offspring that were suppressed by MO. These data suggest that ME is an accessible therapeutic approach for protecting programming effects of MO on offspring metabolic diseases. Moreover, apelin injection mirrored the effect of ME on intestine and exercise-induced apelin/APJ signaling (APJ; apelin receptor), improving metabolic capacities of intestine. In summary, MO impairs placental and fetal intestinal development, which can be prevented by ME. Apelin/APJ signaling has a critical role in mediating the beneficial effects of ME on placenta and fetal intestinal development, improving the metabolic health of offspring

Blocking Microglial Proliferation by CSF-1R Inhibitor Does Not Alter the Neuroprotective Effects of Adoptive Regulatory T Cells in 3xTg Alzheimer’s Disease Mice

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that causes cognitive impairment. Neuroinflammation induced by activated microglia exacerbates AD. Regulatory T cells (Tregs) play roles in limiting neuroinflammation by converting microglial polarization. Therefore, adoptive Treg therapy is considered an attractive option for neurodegenerative disorders. However, the mechanism underlying Treg therapy via microglial modulation is not fully understood. In this study, we sought to determine whether adoptively transferred Tregs were effective when microglia proliferation was inhibited by using GW2580, which is an inhibitor of CSF1R. We found that inhibition of microglial proliferation during Treg transfer did not alter the therapeutic effects of Tregs on cognitive deficits and the accumulation of Aβ and pTAU in 3xTg-AD mice. The expression of pro- and anti-inflammatory markers in the hippocampus of 3xTg mice showed that GW2580 did not affect the inhibition of neuroinflammation by Treg transfer. Additionally, adoptively transferred Tregs were commonly detected in the brain on day 7 after transfer and their levels decreased slowly over 100 days. Our findings suggest that adoptively transferred Tregs can survive longer than 100 days in the brain, suppressing microglial activation and thus alleviating AD pathology. The present study provides valuable evidence to support the prolonged efficacy of adoptive Treg therapy in AD