The Hippo pathway restricts cell growth and proliferation and promotes apoptosis to control organ size. The Drosophila melanogaster isoform of RASSF (Ras association domain family; dRASSF) antagonizes proapoptotic Hippo signaling by inhibiting the binding of the adaptor protein Salvador to the kinase Hippo. Paradoxically, however, dRASSF also functions as a tumor suppressor. In mammals, RASSF1A induces apoptosis by stimulating the mammalian Ste20-like kinases (MSTs) 1 and 2, which are Hippo homologs. Here, we characterize the interaction between MST2 and another mammalian RASSF isoform, RASSF6. When bound to MST2, RASSF6 inhibited MST2 activity to antagonize Hippo signaling. However, RASSF6 caused apoptosis when released from activated MST2 in a manner dependent on WW45, the mammalian Salvador homolog. Thus, RASSF6 antagonizes Hippo signaling and mediates apoptosis through a pathway that is parallel to the canonical Hippo pathway. Our findings suggest that activation of MST2 causes apoptosis through the Hippo pathway, as well as through a RASSF6-mediated pathway.

Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr−/−) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), the brain region known to control thermogenesis in brown adipose tissue (BAT). Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr−/− mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in BAT observed in Oxtr−/− mice. Additionally, increased expression of the β3-adrenergic receptor gene, Adrb3, was observed in BAT. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions.

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BackgroundIron deficiency and underweight are common nutritional problems among young Japanese women, many of whom show unhealthy dietary patterns owing to a desire for thinness. We conducted a cross-sectional analysis of the relationship between iron status, nutritional status, and dietary intake among young Japanese women with underweight to identify dietary risk factors for iron deficiency.MethodsOf the 159 young women (18–29 years of age) enrolled, 77 underweight and 37 normal-weight women were included in the study. They were further categorized into four groups based on quartiles of hemoglobin levels among all participants. Dietary nutrient intake was ascertained using a brief self-administered diet history questionnaire. Blood level of hemoglobin and nutritional biomarkers such as total protein, albumin, insulin-like growth factor-1 (IGF-1), and essential amino acids were measured.ResultsIn underweight, the multiple comparison test showed that dietary intakes of fat, saturated fatty acid, and monosaturated fatty acid were significantly higher and carbohydrate intake was significantly lower in the group with the lowest hemoglobin level, whereas intakes of iron were the same across groups. Multivariate regression coefficients suggested that replacing fat with protein or carbohydrates increased hemoglobin levels under isocaloric conditions. Additionally, significant positive correlations were observed between hemoglobin levels and nutritional biomarkers.ConclusionDietary iron intake did not change across different hemoglobin groups among Japanese underweight women. However, our results suggested that an imbalanced dietary macronutrient induces anabolic status and hemoglobin synthesis deterioration among them. Especially, a higher fat intake may be a risk factor for lower hemoglobin.