Although maternal nurturing behavior is extremely important for the preservation of a species, our knowledge of the biological underpinnings of these behaviors is insufficient. Here we show that the degree of a mother's nurturing behavior is regulated by factors present during her own fetal development. We found that Cin85-deficient () mother mice had reduced pituitary hormone prolactin (PRL) secretion as a result of excessive dopamine signaling in the brain. Their offspring matured normally and produced their own pups; however, nurturing behaviors such as pup retrieval and nursing were strongly inhibited. Surprisingly, when WT embryos were transplanted into the fallopian tubes of mice, they also exhibited inhibited nurturing behavior as adults. Conversely, when embryos were transplanted into the fallopian tubes of WT mice, the resultant pups exhibited normal nurturing behaviors as adults. When PRL was administered to mice during late pregnancy, a higher proportion of the resultant pups exhibited nurturing behaviors as adults. This correlates with our findings that neural circuitry associated with nurturing behaviors was less active in pups born to mothers, but PRL administration to mothers restored neural activity to normal levels. These results suggest that the prenatal period is extremely important in determining the expression of nurturing behaviors in the subsequent generation, and that maternal PRL is one of the critical factors for expression. In conclusion, perinatally secreted maternal PRL affects the expression of nurturing behaviors not only in a mother, but also in her pups when they have reached adulthood.
Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1β (HNF-1α/β) at −84/−68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1. Angiopoietin-like proteins (Angptls) are a family of proteins structurally similar to angiopoietins. Previous reports on Angptls have identified them as key regulators of circulating triglyceride(TG) levels, implicating them as potential new drug targets for treatment of metabolic syndrome 1,2 ANGPTL8, alternatively called the TD26, lipasin, C19orf80, or RIFL (refeeding induced fat and liver) gene, was originally identified as a novel adipocyte-enriched insulin target gene with a role in lipid metabolism 3-5. (A previously reported identification of Angptl8 as 'Betatrophin, ' a factor controlling the differentiation and proliferation of pancreatic β cells 6 , retracted article), was later determined to be incorrect 7-10. Ren et al. found that the RIFL gene encodes a predicted protein of 22kD with homology to Angptl3 3 , Furthemore, the murine white and brown adipose tissue (WAT and BAT) and liver were highly enriched in the RIFL transcript, and the level increased ~80-fold in WAT and 12-fold in liver, following 8 h refeedings of fasting mice 3. Several studies with Angptl8-deficient or Angptl8-overxpressing rodents have demonstrated that Angptl8, which is homologous to the N-terminal domain of Angptl3, modulates circulating TG clearance by inhibiting lipoprotein lipase (LPL) activity in the presence of Angptl3 3-5,7,8,11. Recent human studies have shown that serum ANGPTL8 levels are increased in subjects with Type 1 diabetes (T1D) 12 , obesity 13 , Type 2 diabet...
Elucidating the mechanisms underlying nurturing and neglect behaviors is meaningful but challenging. Recently, we found that CIN85-deficient mice had reduced pituitary hormone prolactin secretion during late pregnancy, and their pups later showed an inhibited nurturing behavior. To examine whether this phenomenon could be reproduced in normal mice and not just CIN85-deficient mice, we investigated the nurturing behavior of offspring born to mothers whose blood prolactin levels had been reduced by bromocriptine administration during late pregnancy. First, to determine when bromocriptine treatment should be started, we investigated the detailed changes in blood prolactin levels in late pregnancy in mice, resulting in the identification of the prepartum prolactin surge. Furthermore, prolactin receptors in the fetal hypothalamus were expressed to the same extent as in the adult hypothalamus. Treatment with bromocriptine decreased the plasma concentrations of prolactin to the basal range throughout late pregnancy. However, against expectations, the proportion of the resultant pups exhibiting nurturing behaviors as adults was as high as that in the mice without bromocriptine treatment. In conclusion, the elimination of prolactin secretion during late pregnancy alone does not induce neglect-like behavior in offspring, suggesting that CIN85-deficient mice appear to involve another factor due to CIN85 deficiency besides prolactin deficiency.
Iron metabolism is closely associated with the pathogenesis of obesity. However, the mechanism of the iron-dependent regulation of adipocyte differentiation remains unclear. Here, we show that iron is essential for rewriting of epigenetic marks during adipocyte differentiation. Iron supply through lysosome-mediated ferritinophagy was found to be crucial during the early stage of adipocyte differentiation, and iron deficiency during this period suppressed subsequent terminal differentiation. This was associated with demethylation of both repressive histone marks and DNA in the genomic regions of adipocyte differentiation-associated genes, including Pparg, which encodes PPARγ, the master regulator of adipocyte differentiation. In addition, we identified several epigenetic demethylases to be responsible for iron-dependent adipocyte differentiation, with the histone demethylase jumonji domain-containing 1A and the DNA demethylase ten-eleven translocation 2 as the major enzymes. The interrelationship between repressive histone marks and DNA methylation was indicated by an integrated genome-wide association analysis, and was also supported by the findings that both histone and DNA demethylation were suppressed by either the inhibition of lysosomal ferritin flux or the knockdown of iron chaperone poly(rC)-binding protein 2. In summary, epigenetic regulations through iron-dependent control of epigenetic enzyme activities play an important role in the organized gene expression mechanisms of adipogenesis.
α-Ketoglutarate (α-KG) also known as 2-oxoglutarate (2-OG) is an intermediate metabolite in the tricarboxylic acid (TCA) cycle and is also produced by the deamination of glutamate. It is an indispensable cofactor for a series of 2oxoglutarate-dependent oxygenases including epigenetic modifiers such as ten-eleven translocation DNA demethylases (TETs) and JmjC domain-containing histone demethylases (JMJDs). Since these epigenetic enzymes target genomic DNA and histone in the nucleus, the nuclear concentration of α-KG would affect the levels of transcription by modulating the activity of the epigenetic enzymes. Thus, it is of great interest to measure the nuclear concentration of α-KG to elucidate the regulatory mechanism of these enzymes. Here, we report a novel fluorescence resonance energy transfer (FRET)-based biosensor with multiple nuclear localization signals (NLSs) to measure the nuclear concentration of α-KG. The probe contains the α-KGbinding GAF domain of NifA protein from Azotobacter vinelandii fused with EYFP and ECFP. Treatment of 3T3-L1 preadipocytes expressing this probe with either dimethyl-2-oxoglutarate (dimethyl-2-OG), a cell-permeable 2-OG derivative, or citrate elicited time-and dose-dependent changes in the FRET ratio, proving that this probe functions as an α-KG sensor. Measurement of the nuclear α-KG levels in the 3T3-L1 cells stably expressing the probe during adipocyte differentiation revealed that the nuclear concentration of α-KG increased in the early stage of differentiation and remained high thereafter. Thus, this nuclear-localized α-KG probe is a powerful tool for real-time monitoring of α-KG concentrations with subcellular resolution in living cells and is useful for elucidating the regulatory mechanisms of epigenetic enzymes.
The Cbl-interacting protein of 85 kDa (CIN85) belongs to a family of ubiquitously expressed adaptor/scaffold proteins. CIN85 interacts with endocytic proteins involved in various receptor signaling pathways. Despite extensive investigations of CIN85 in receptor trafficking, little is known about its functions in vivo. Mice deficient in brain-specific CIN85 expression show hyperactive phenotypes, which in many ways resemble the behavioural aberrations displayed in human beings affected by attention deficit/hyperactivity disorder (ADHD), a disorder strongly associated with abnormal dopamine signaling. ADHD is a neurobehavioural disorder characterized by either significant difficulties of inattention or hyperactivity and impulsiveness or a combination of the two. While genetic factors are strongly implicated in the etiology of ADHD, the genes responsible for ADHD are unknown. Here, we review the recent progress of CIN85 study and the possibility of ADHD onset owing to CIN85 defect in the brain.
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