Influence of dynamic load and water on energy accumulation and dissipation in sandstone.

In various engineering projects such as mineral extraction, hydropower resource utilization, railway construction, and geological hazard mitigation, rock engineering is often encountered. Furthermore, dynamic loads and moisture content exert notable influence on the energy transformation processes within rocks. Yet, the specific interplay of dynamic loading and water's impact on the energy conversion mechanism within the sandstone remains unexplored. To address this gap, this study conducted impact loading experiments on sandstone, elucidating the rock's mechanical response under these conditions and unraveling the underlying energy conversion mechanisms. It was observed that the strength of sandstone exhibits a direct correlation with impact velocity. Moreover, employing energy calculation principles, we established a connection between moisture content and the sandstone's internal energy conversion properties. The study also delved into the microscopic fracture mechanisms within the sandstone, ultimately concluding that both water content and dynamic loading have a significant impact on these microscopic fracture mechanisms.

Material basis and action mechanism of Euryale Ferox Salisb in preventing and treating diabetic kidney disease.

The aim of this study was to determine the chemical structure and mechanism of action of Euryale ferox Salisb (ES) in the prevention and treatment of diabetic kidney disease (DKD). The TCMSP, SymMap V2, CTD, DisGeNET, and GeneCards databases were searched for ES components, targets, and DKD targets using the network pharmacology method to identify common drug-disease targets. PPI analysis was used to identify hub genes, which were then followed by DKD clinical relevance, GO, KEGG analysis, and transcription factor prediction. Finally, molecular docking was performed. We discovered 24 components of ES and 72 objectives of ES, 9 of which were clinically relevant and primarily regulated by transcription factors such as HNF4A and PPARG. They are involved primarily in signal transduction, inflammatory responses, TNF regulation, apoptosis, MAPK, and other signaling pathways. The main components are oleic acid targeting the protein encoded by PPARA, LPL, FABP1, and vitamin E binding the protein encoded by MAPK1, TGFB1. In general, this approach provides an effective strategy in which ES acts primarily against DKD through oleic acid and vitamin E, targeting the protein encoded by PPARA, LPL, FABP1, MAPK1 to regulate TNF, apoptosis, MAPK, and other signaling pathways. PRACTICAL APPLICATIONS: Euryale ferox Salisb (ES) is well known for its use in medicine and food. Furthermore, ES contains many nutrients, whose pharmacological properties, including antidepressant, antioxidant, and anti-diabetic action, have been extensively demonstrated by numerous studies. In this article, through network pharmacology combined with clinical correlation analysis and molecular docking, the target and mechanism of ES in the treatment of diabetic kidney disease (DKD) were discussed, which clarified its mechanism at the molecular level. Provides a reference for the further development and utilization of ES.

Stable structures and superconducting properties of Ca-La-H compounds under pressure.

The calcium hydrides and lanthanum hydrides under high pressures have been reported to have good superconducting properties with high-TC. In this work, the structures and superconductivities of Ca-La-H ternary hydrides have been studied by genetic algorithm and density functional theory calculations. Our results show that at the pressure range of 100-300 GPa, the most stable structure of CaLaH12has aCmmmsymmetry, in which there is a H24hydrogen cage. It can be expected to have high possibility to be synthesized due to its large stability. Furthermore, the predictedTCof theCmmm-CaLaH12structure is about 140 K at 150 GPa, and when the pressure decreases to 30 GPa, the CaLaH12structure with aC2/msymmetry has a predictedTCof about 49 K. The CaLaH12is suggested to be a stable good superconductor with large stability and performs well at relatively low pressures.

Study on superconducting Li-Se-H hydrides.

The structures, stabilities and superconducting properties of LiSeHn (n = 4-10) hydrides at 150-300 GPa were studied by the genetic algorithm (GA) and DFT calculation method. Three stable stoichiometries of LiSeH4, LiSeH6 and LiSeH10 were uncovered under high pressure. Four other metastable stoichiometries of LiSeH5, LiSeH7, LiSeH8, and LiSeH9 were also studied. By analyzing the electronic band structure and electronic density of states, C2 LiSeH4, Pmm2 LiSeH6 and C2 LiSeH10 were all found to be metal phases above 150 GPa. Electron-phonon coupling calculations showed that C2 LiSeH4 and Pmm2 LiSeH6 were promising superconductors. The predicted Tc values of C2 LiSeH4 and Pmm2 LiSeH6 were 77 K at 200 GPa and 111 K at 250 GPa, respectively.

Fertility factors affect the vaginal microbiome in women of reproductive age.

PROBLEM: For women of reproductive age, achieving a successful pregnancy requires both the normal functioning of reproductive endocrine and the health of the reproductive tract environment. We aimed to study how these fertility factors, such as female age, baseline sexual hormone levels, tubal patency, and vaginal pH, affect the composition of vaginal microbiome. METHOD OF STUDY: The 16S rRNA sequencing was carried on vaginal microbiome samples from 85 women of reproductive age without vaginal infections or reproductive endocrine diseases. The detailed correlations between fertility factors and vaginal microbiome were quantified by Spearman's rank tests. A linear discriminant analysis was carried out to explore the effects of fertility factors on the relative abundances of vaginal bacterial species. RESULTS: The vaginal pH, levels of basal E2, LH, and FSH all had significant effects on the distribution of vaginal microbiome. The relative abundances of vaginal bacterial species, including Escherichia coli, Streptococcus agalactiae, and Prevotella intermedia, were significantly different due to the host's state of reproductive endocrine and tubal patency. It was worth noting that women with tubal obstruction, or prolonged menstrual cycle, or antral follicle count >15, or vaginal pH > 4.5 all had a higher abundance of Escherichia coli in vagina. CONCLUSION: The fertility factors associated with the reproductive endocrine and the genital tract environment affected vaginal microbiome in women of reproductive age. The species Escherichia coli, Streptococcus agalactiae, Prevotella intermedia, etc could be used as biomarkers to reflect the pathological state of reproductive endocrine and genital tract.

All-Optical Volumetric Physiology for Connectomics in Dense Neuronal Structures.

All-optical physiology (AOP) manipulates and reports neuronal activities with light, allowing for interrogation of neuronal functional connections with high spatiotemporal resolution. However, contemporary high-speed AOP platforms are limited to single-depth or discrete multi-plane recordings that are not suitable for studying functional connections among densely packed small neurons, such as neurons in Drosophila brains. Here, we constructed a 3D AOP platform by incorporating single-photon point stimulation and two-photon high-speed volumetric recordings with a tunable acoustic gradient-index (TAG) lens. We demonstrated the platform effectiveness by studying the anterior visual pathway (AVP) of Drosophila. We achieved functional observation of spatiotemporal coding and the strengths of calcium-sensitive connections between anterior optic tubercle (AOTU) sub-compartments and >70 tightly assembled 2-µm bulb (BU) microglomeruli in 3D coordinates with a single trial. Our work aids the establishment of in vivo 3D functional connectomes in neuron-dense brain areas.

Bisphenol A stimulates steroidogenic acute regulatory protein expression via an unknown mechanism in adrenal cortical cells.

Bisphenol A (BPA) is one of the most widespread endocrine disrupting chemicals in the environment. Exposure to BPA is known to be associated with disruption of steroidogenesis in reproductive tissues, but little is known about its effects on the adrenal gland. We previously showed that prenatal BPA exposure resulted in elevated plasma corticosterone levels concomitant with increased adrenal levels of steroidogenic acute regulatory protein (StAR), the rate-limiting step in steroidogenesis, in adult female mouse offspring. However, the molecular mechanisms underlying the BPA-induced StAR protein expression in the adrenal gland remain unknown. Therefore, the current study was designed to address this important question using the human cortical cell line, H295A cells, as an in vitro model system. We found that: (1) BPA increased StAR protein levels in a dose-dependent manner; (2) both estrogen receptor alpha (ERα)- and ERß-specific agonists mimicked while the ER antagonist ICI abrogated the stimulatory effects of BPA on StAR protein levels; and (3) BPA did not alter StAR messenger RNA, 37kDa preprotein or protein half-life. Taken together, these findings demonstrate that BPA increases StAR protein levels through an unknown mechanism independent of StAR gene transcription, translation, and protein half-life. Furthermore, such effects are likely mediated by ERα and/or ERß.

Bisphenol A stimulates adrenal cortical cell proliferation via ERß-mediated activation of the sonic hedgehog signalling pathway.

We previously demonstrated that prenatal exposure to bisphenol A (BPA) resulted in increased adrenal gland weight independent of changes in plasma ACTH levels in adult mouse offspring. This finding suggested that BPA exposure likely had a direct effect on adrenal development. Given that (1) sonic hedgehog (Shh) signaling is essential for adrenal development; (2) deletion of the Shh gene in mice results in adrenal hypoplasia; (3) BPA is known to signal through estrogen receptor ß (ERß); and (4) ERß is highly expressed in adrenal glands; we hypothesized that BPA stimulates adrenal cell proliferation via ERß-mediated activation of the Shh pathway. To test this hypothesis, the human adrenal cell line, H295A cells, was used as an in vitro model system. Our main findings were: (1) BPA increased cell number and protein levels of proliferating cell nuclear antigen (PCNA; a universal marker of cell proliferation), cyclin D1 and D2 (key proliferation factors), as well as Shh and its key transcriptional regulator Gli1; (2) cyclopamine, a Shh pathway inhibitor, blocked these stimulatory effects of BPA on cell proliferation; (3) BPA increased the nuclear translocation of ERß; and (4) the ERß-specific agonist DPN mimicked while the ERß-specific antagonist PHTPP abrogated the stimulatory effects of BPA on cell proliferation and Shh signaling. Taken together, these findings demonstrate that BPA stimulates adrenal cell proliferation likely through ERß-mediated activation of the Shh signaling pathway. Thus, the present study provides novel insights into the molecular mechanisms underlying our previously reported BPA-induced aberrant adrenal phenotype.

The Gut Microbiota of Healthy Aged Chinese Is Similar to That of the Healthy Young.

The microbiota of the aged is variously described as being more or less diverse than that of younger cohorts, but the comparison groups used and the definitions of the aged population differ between experiments. The differences are often described by null hypothesis statistical tests, which are notoriously irreproducible when dealing with large multivariate samples. We collected and examined the gut microbiota of a cross-sectional cohort of more than 1,000 very healthy Chinese individuals who spanned ages from 3 to over 100 years. The analysis of 16S rRNA gene sequencing results used a compositional data analysis paradigm coupled with measures of effect size, where ordination, differential abundance, and correlation can be explored and analyzed in a unified and reproducible framework. Our analysis showed several surprising results compared to other cohorts. First, the overall microbiota composition of the healthy aged group was similar to that of people decades younger. Second, the major differences between groups in the gut microbiota profiles were found before age 20. Third, the gut microbiota differed little between individuals from the ages of 30 to >100. Fourth, the gut microbiota of males appeared to be more variable than that of females. Taken together, the present findings suggest that the microbiota of the healthy aged in this cross-sectional study differ little from that of the healthy young in the same population, although the minor variations that do exist depend upon the comparison cohort. IMPORTANCE We report the large-scale use of compositional data analysis to establish a baseline microbiota composition in an extremely healthy cohort of the Chinese population. This baseline will serve for comparison for future cohorts with chronic or acute disease. In addition to the expected difference in the microbiota of children and adults, we found that the microbiota of the elderly in this population was similar in almost all respects to that of healthy people in the same population who are scores of years younger. We speculate that this similarity is a consequence of an active healthy lifestyle and diet, although cause and effect cannot be ascribed in this (or any other) cross-sectional design. One surprising result was that the gut microbiota of persons in their 20s was distinct from those of other age cohorts, and this result was replicated, suggesting that it is a reproducible finding and distinct from those of other populations.

Bisphenol A suppresses glucocorticoid target gene (ENaCγ) expression via a novel ERß/NF-κB/GR signalling pathway in lung epithelial cells.

We previously demonstrated that prenatal exposure to Bisphenol A (BPA) disrupts fetal lung maturation likely through the glucocorticoid signalling pathway, but the precise molecular mechanisms remain obscure. Given that BPA diminished the expression of epithelial sodium channel-γ (ENaCγ), a well-known glucocorticoid receptor (GR) target gene, in fetal lungs, we used this GR target gene to delineate the molecular pathway through which BPA exerts its effects on lung cells. The A549 lung epithelial cell line was used as an in vitro model system. As a first step, we validated our in vitro cell model by demonstrating a robust concentration-dependent suppression of ENaCγ expression following BPA exposure. We also showed that both dexamethasone and siRNA-mediated knockdown of GR expression blocked/abrogated the inhibitory effects of BPA on ENaCγ expression, suggesting that BPA repressed ENaCγ expression via inhibition of GR activity. Given the well-known antagonistic interactions between the pro-inflammatory transcriptional factor NF-κB and GR, we then showed that BPA inhibited GR activity through the activation of NF-κB. Lastly, since BPA is known to function as a pro-inflammatory factor via the estrogen receptor ß (ERß), we provided evidence that BPA signals through ERß to activate the NF-κB signalling pathway. Taken together, these findings demonstrate that BPA acts on ERß to activate the NF-κB signalling pathway, which in turn leads to diminished GR activity and consequent repression of ENaCγ expression in lung epithelial cells. Thus, our present study reveals a novel BPA signalling pathway that involves ERß, NF-κB and GR.

Prenatal exposure to bisphenol A disrupts adrenal steroidogenesis in adult mouse offspring.

The present study sought to determine if prenatal exposure to bisphenol A (BPA) alters adrenal steroidogenesis in adult offspring. Pregnant mice were exposed to BPA (25mg BPA/kg food pellet) via diet from day 7 to the end of pregnancy. At eight weeks of age, offsprings were sacrificed, blood samples and adrenal glands were collected for hormone assays and western blot analysis, respectively. We found that: (1) BPA increased adrenal gland weight in both males and females; (2) although BPA elevated plasma corticosterone levels in both sexes, it stimulated the expression of StAR and cyp11A1, the two rate-limiting factors in the steroidogenic pathway, only in female adrenal glands; and interestingly (3) BPA did not alter plasma ACTH levels or adrenal expression of the key steroidogenic transcription factor SF-1 in either sex. Taken together, the present study provides novel insights into the long-term consequences of developmental BPA exposure on adrenal steroidogenesis.

Prenatal exposure to bisphenol A alters mouse fetal pancreatic morphology and islet composition.

BACKGROUND: Exposure to bisphenol A (BPA), an endocrine disrupting chemical, during gestation is associated with a variety of metabolic dysfunctions in adulthood, including hyperinsulinemia, glucose intolerance and insulin resistance. These modifications in glucose homeostasis largely stem from alterations in pancreatic function. However, the effects of BPA on the fetal pancreas have never been explored. The present study addressed this important question by examining the effects of prenatal BPA exposure on the mouse fetal pancreatic development. MATERIALS AND METHODS: Pregnant mice were fed a BPA diet (25 mg BPA/kg diet) from embryonic day 7.5 (E7.5) to E18.5. At E18.5, fetal pancreata were collected and analyzed for morphological changes in the endocrine pancreas such as islet size, number and ß and α cell distribution. RESULTS: We showed that BPA exposed fetal pancreata had a greater number of islet-cell clusters (ICCs; <300 µm(2); p<0.05) compared with controls. Furthermore, immunohistochemical analysis revealed that prenatal BPA exposure increased both glucagon expression in islets and the numbers of glucagon-expressing islet-cell clusters (p<0.05). CONCLUSION: Considering that ICCs represent the initial stages of islet development in the fetal pancreas, our findings suggest that BPA promotes islet differentiation or delays the conversion of ICCs into mature islets. Moreover, the increase in glucagon expression suggests a potential alteration in the α:ß-cell ratio in islets, which may have significant implications for the fetal pancreas both structurally and functionally. This study provides novel insight into the effects of BPA exposure on the fetal pancreata, indicating alterations in glucagon expression in islets and ICCs.

Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation.

Adipose tissue expansion, resulting from adipocyte hyperplasia and/or hypertrophy, is a hallmark of obesity. Adipocytes are derived from mesenchymal stem cells (MSCs) through adipogenesis, a process involving three key steps: proliferation, commitment and differentiation. Although studies have elaborated on the mechanisms regulating adipocyte commitment and differentiation, the factors that control MSC proliferation remain largely unknown. Previously, we demonstrated that bone morphogenetic protein 3 (Bmp3), the expression of which was upregulated in our rat model of hyperplasic visceral adiposity, potently stimulated MSC proliferation. In the present study, we investigate the molecular target of Bmp3. We conducted DNA microarray analysis on MSCs treated with and without Bmp3 and identified WNT1-inducible signaling pathway protein 1 (Wisp1) as a differentially expressed gene, whose expression was upregulated 3.7-fold by Bmp3. Wisp1 is a proliferative agent in various non-adipose cell types and is implicated in adipogenesis. Therefore, we tested the hypothesis that Wisp1 mediates Bmp3 stimulation of MSC proliferation. We showed that Bmp3 increased the expression of Wisp1 as early as 3 h following Bmp3 treatment in MSCs. Importantly, the upregulated Wisp1 expression preceded Bmp3-induced MSC proliferation, as determined by [(3)H]-thymidine incorporation. Furthermore, treatment of MSCs with recombinant Wisp1 led to a concentration-dependent increase in [(3)H]-thymidine incorporation with a maximal increase of 300%. In addition, siRNA-mediated knockdown of Wisp1 expression attenuated Bmp3-induced MSC proliferation. Taken together, our present findings reveal Wisp1 as a novel target of Bmp3 and suggest that the Bmp3/Wisp1 signaling pathway play a key role in MSC proliferation, and consequently adipogenesis.

Prenatal Exposure to Bisphenol A Disrupts Mouse Fetal Liver Maturation in a Sex-Specific Manner.

Bisphenol A (BPA) is one of the most prevalent endocrine disrupting chemicals in the environment. Developmental exposure to BPA is known to be associated with liver dysfunction and diseases, such as hepatic steatosis, liver tumors, metabolic syndrome, and altered hepatic gene expression, and DNA methylation profiles. However, the effects of BPA on rodent liver development are unknown. The present study was undertaken to address this important question using the mouse as an experimental model. Pregnant mice were exposed to BPA via diet from embryonic day 7.5 (E7.5) to E18.5. At E18.5, fetal livers were collected, and analyzed for changes in the expression of key hepatocyte maturation markers. We found the following significant alterations in BPA-exposed female but not male fetal livers: (a) levels of the mature hepatocyte markers, albumin and glycogen synthase proteins, were decreased (-65% and -40%, respectively); (b) levels of the immature hepatocyte marker, α-fetoprotein, were increased (+43%); (c) the level of C/EBP-α protein, the master transcription factor essential for hepatocyte maturation, was down-regulated (-50%); and (d) the level of PCNA protein (marker of proliferation) was elevated (+40%), while that of caspase-3 protein and activity (markers of apoptosis) was reduced (-40% and -55%, respectively), suggestive of a perturbed balance between cell proliferation and apoptosis in BPA-exposed female fetuses. Taken together, these findings demonstrate that prenatal exposure to BPA disrupts the mouse fetal liver maturation in a sex-specific manner, and suggest a fetal origin for BPA-induced hepatic dysfunction and diseases.

Prenatal exposure to bisphenol A disrupts mouse fetal lung development.

Developmental exposure to bisphenol A (BPA) is associated with lung dysfunction and diseases. However, it is unknown if this association has a fetal origin. The present study addressed this important question by examining the effects of BPA on fetal lung development. BPA was administered to pregnant mice via diet from embryonic day (E) 7.5 to E18.5. Fetal lungs were analyzed at E18.5 for changes in structure and expression of key molecular markers of lung maturation. Our main findings were as follows: BPA severely retards fetal lung maturation, as evidenced by diminished alveolar airspace (15% of control) and thickened septa, hallmarks of lung immaturity; this immaturity is characterized by aberrant alveolar epithelial type I cell differentiation because expression of the type I cell marker, aquaporin 5, but not type II cell markers, is dramatically reduced (16% of control); and the effects of BPA are likely mediated through the glucocorticoid signaling pathway because the expression of epithelial sodium channel γ and glutathione peroxidase, 2 well-known glucocorticoid target genes, is down-regulated in BPA-exposed fetal lungs, and, importantly, maternal dexamethasone administration rescues the lung immaturity phenotype. Taken together, these findings demonstrate that BPA disrupts fetal lung maturation, thus suggesting a fetal origin for BPA-induced lung diseases.

Bisphenol A disrupts gene expression in human placental trophoblast cells.

This study examined the effect of bisphenol A (BPA) on human placental gene expression using primary trophoblast cells as an in vitro model system. Trophoblast cells were isolated from human placentas at term, cultured and then exposed to environmentally relevant concentrations of BPA (0.1-2 µg/ml) for up to 24h, after which levels of 11ß-HSD2 mRNA, protein and activity were determined by standard radiometric conversion assay, western blotting, and qRT-PCR, respectively. The mRNA levels of several other prominent placental hormones/factors were also assessed by qRT-PCR. BPA dramatically increased levels of 11ß-HSD2 activity, protein and mRNA in a time- and concentration-dependent manner (> 4-fold). BPA also augmented aromatase, glucose transporter-1, CRH, and hCG mRNA levels while reducing the level of leptin mRNA. These findings demonstrate that BPA severely disrupts human placental gene expression in vitro, which suggests that exposure to BPA may contribute to altered placental function and consequent pregnancy complications.

The ERK1/2 signaling pathway regulates 11beta-hydroxysteroid dehydrogenase type 2 expression in human trophoblast cells through a transcriptional mechanism.

The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by the HSD11B2 gene) plays a key role in fetal development, but its regulation is incompletely understood. We previously demonstrated that p38 MAPK was a positive regulator of placental 11beta-HSD2. However, it remains unknown if the other two MAPKs, ERK1/2 and JNK, were also involved. In the present study, we identified ERK1/2 as an important regulator of placental 11beta-HSD2. We showed that inhibition of ERK1/2 with the pharmacological inhibitor U0126 led to a 3-fold increase in 11beta-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. In contrast, the JNK inhibitor SP600125 had no effect. Furthermore, U0126 increased the HSD11B2 promoter activity by 300%, indicating that ERK1/2 regulates placental 11beta-HSD2 expression through a transcriptional mechanism. Importantly, siRNA-mediated knockdown of ERK1/2 caused a similar increase in 11beta-HSD2 protein. In addition, given that we previously showed that cadmium reduced placental 11beta-HSD2 expression via a transcriptional mechanism, but the signal transduction pathways involved remain unclear, we also addressed this question and found that treatment of trophoblast cells with cadmium led to rapid activation of ERK1/2. Importantly, U0126 completely abrogated the inhibitory effects of cadmium on placental 11beta-HSD2. Taken together, the present study not only identifies the ERK1/2 signaling pathway as a potent negative regulator of placental 11beta-HSD2 but also demonstrates that this pathway mediates cadmium repression of placental 11beta-HSD2. Thus, our present study reveals 11beta-HSD2 as an important target through which ERK1/2 may regulate human placental function and consequently fetal development.

Metallothionein-I- and -II-deficient mice display increased susceptibility to cadmium-induced fetal growth restriction.

Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. The placenta is the main organ known to protect the fetus from environmental toxins such as cadmium. In this study, we examine the role of the two key placental factors in cadmium-induced FGR. The first is placental enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is known to protect the fetus from exposure to high cortisol levels and subsequently FGR, and the second the cadmium binding/sequestering proteins metallotheionein (MT)-I and -II. Using the MT-I/II(-/-) mouse model, pregnant mice were administered cadmium, following which pups and placentas were collected and examined. MT-I/II(-/-) pups exposed to cadmium were significantly growth restricted, but neither placental weight nor 11ß-HSD2 was altered. Although cadmium administration did not result in any visible structural changes in the placenta, increased apoptosis was detected in MT-I/II(-/-) placentas following cadmium exposure, with a significant increase in levels of both p53 and caspase 3 proteins. Additionally, glucose transporter (GLUT1) was significantly reduced in MT-I/II(-/-) placentas of pups exposed to cadmium, whereas zinc transporter (ZnT-1) remained unaltered. Taken together, these results demonstrate that MT-I/II(-/-) mice are more vulnerable to cadmium-induced FGR. The present data also suggest that increased apoptosis and reduced GLUT1 expression in the placenta contribute to the molecular mechanisms underlying cadmium-induced FGR.

In utero programming of later adiposity: the role of fetal growth restriction.

Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor-γ (PPARγ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation.

Neuropeptide Y potentiates beta-adrenergic stimulation of lipolysis in 3T3-L1 adipocytes.

Recently, we have shown that neuropeptide Y (NPY) is produced and upregulated in visceral adipose tissue of an early-life programmed rat model of central obesity. Moreover, we have demonstrated that NPY promotes proliferation of adipocyte precursor cells and contributes to the pathogenesis of obesity. However, the role of NPY in regulating adipocyte metabolism is poorly understood. The present study was designed to examine the effects of NPY on adipocyte metabolic function using 3T3-L1 adipocytes as an in vitro cell model system. We found that although it did not affect basal lipolysis, NPY potentiated isoproterenol (a ß-adrenergic receptor agonist) stimulated lipolysis. Furthermore, this potentiation occurred upstream of adenylyl cyclase, since NPY did not enhance forskolin (an activator of adenylyl cyclase) stimulated lipolysis. In addition, NPY also augmented isoproterenol-stimulated phosphorylation of hormone sensitive lipase. In contrast, NPY did not alter the expression of several key lipolytic and lipogenic enzymes/proteins. Taken together, our results revealed a novel cross talk between the NPY and ß-adrenergic signaling pathways in regulating lipolysis. Thus, the present findings add a new dimension to the dynamic role NPY plays in regulating energy balance.