STUDY QUESTIONHow does a maternal diabetic hyperadiponectineamia affect signal transduction and lipid metabolism in rabbit preimplantation blastocysts?SUMMARY ANSWERIn a diabetic pregnancy increased levels of adiponectin led to a switch in embryonic metabolism towards a fatty acid-dependent energy metabolism, mainly affecting genes that are responsible for fatty acid uptake and turnover.WHAT IS KNOWN ALREADYAlthough studies in cell culture experiments have shown that adiponectin is able to regulate lipid metabolism via 5′-AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα), data on the effects of adiponectin on embryonic lipid metabolism are not available. In a diabetic pregnancy in rabbits, maternal adiponectin levels are elevated fourfold and are accompanied by an increase in intracellular lipid droplets in blastocysts, implying consequences for the embryonic hormonal and metabolic environment.STUDY DESIGN, SIZE, DURATIONRabbit blastocysts were cultured in vitro with adiponectin (1 μg/ml) and with the specific AMPK-inhibitor Compound C for 15 min, 1 h and 4 h (N ≥ 3 independent experiments: for RNA analysis, n ≥ 4 blastocysts per treatment group; for protein analysis three blastocysts pooled per sample and three samples used per experiment). Adiponectin signalling was verified in blastocysts grown in vivo from diabetic rabbits with a hyperadiponectinaemia (N ≥ 3 independent experiments, n ≥ 4 samples per treatment group, eight blastocysts pooled per sample).PARTICIPANTS/MATERIALS, SETTING, METHODSIn these blastocysts, expression of molecules involved in adiponectin signalling [adaptor protein 1 (APPL1), AMPK, acetyl-CoA carboxylase (ACC), p38 mitogen-activated protein kinases (p38 MAPK)], lipid metabolism [PPARα, cluster of differentiation 36 (CD36), fatty acid transport protein 4 (FATP4), fatty acid binding protein (FABP4), carnitine palmityl transferase 1 (CPT1), hormone-senstive lipase (HSL), lipoprotein lipase (LPL)] and members of the insulin/insulin-like growth factor (IGF)-system [IGF1, IGF2, insulin receptor (InsR), IGF1 receptor (IGF1R)] were analyzed by quantitative RT-PCR and western blot. Analyses were performed in both models, i.e. adiponectin stimulated blastocysts (in vitro) and in blastocysts grown in vivo under increased adiponectin levels caused by a maternal diabetes mellitus.MAIN RESULTS AND THE ROLE OF CHANCEIn both in vitro and in vivo models adiponectin increased AMPK and ACC phosphorylation, followed by an activation of the transcription factor PPARα, and CPT1, the key enzyme of β-oxidation (all P < 0.05 versus control). Moreover, mRNA levels of the fatty acid transporters CD36, FATP4 and FABP4, and HSL were upregulated by adiponectin/AMPK signalling (all P < 0.05 versus control). Under diabetic developmental conditions the amount of p38 MAPK was upregulated (P < 0.01 versus non-diabetic), which was not observed in blastocysts cultured in vitro with adiponectin, indicating that the elevated p38 MAPK was not related to adiponectin. However,...
According to the "developmental origin of health and disease" hypothesis, the metabolic set points of glucose and lipid metabolism are determined prenatally. In the case of a diabetic pregnancy, the embryo is exposed to higher glucose and lipid concentrations as early as during preimplantation development. We used the rabbit to study the effect of maternal diabetes type 1 on lipid accumulation and expression of lipogenic markers in preimplantation blastocysts. Accompanied by elevated triglyceride and glucose levels in the maternal blood, embryos from diabetic rabbits showed a massive intracellular lipid accumulation and increased expression of fatty acid transporter 4, fatty acid-binding protein 4, perilipin/adipophilin, and maturation of sterol-regulated element binding protein. However, expression of fatty acid synthase, a key enzyme for de novo synthesis of fatty acids, was not altered in vivo. During a short time in vitro culture of rabbit blastocysts, the accumulation of lipid droplets and expression of lipogenic markers were directly correlated with increasing glucose concentration, indicating that hyperglycemia leads to increased lipogenesis in the preimplantation embryo. Our study shows the decisive effect of glucose as the determining factor for fatty acid metabolism and intracellular lipid accumulation in preimplantation embryos.
During the first days of development the preimplantation embryo is supplied with nutrients from the surrounding milieu. Maternal diabetes mellitus affects the uterine microenvironment, leading to a metabolic adaptation processes in the embryo. We analysed embryonic fatty acid (FA) profiles and expression of processing genes in rabbit blastocysts, separately in embryoblasts and trophoblasts, to determine the potential consequences of maternal diabetes mellitus on intracellular FA metabolism. Insulin-dependent diabetes was induced by alloxan in female rabbits. On day 6 post coitum, FA profiles in blastocysts (embryoblast, trophoblast and blastocoel fluid) and maternal blood were analysed by gas chromatography. The expression levels of molecules involved in FA elongation (fatty acid elongases, ELOVLs) and desaturation (fatty acid desaturases, FADSs) were measured in embryoblast and trophoblast. Maternal diabetes mellitus influenced the FA profile in maternal plasma and blastocysts. Independent from metabolic changes, rabbit blastocysts contained a higher level of saturated fatty acids (SFAs) and a lower level of polyunsaturated fatty acids (PUFAs) compared to the FA profile of the maternal plasma. Furthermore, the FA profile was altered in the embryoblast and trophoblast, differently. While SFAs (palmitic and stearic acid) were elevated in embryoblast of diabetic rabbits, PUFAs, such as docosahexaenoic acid, were decreased. In contrast, in the trophoblast, lower levels of SFAs and higher levels of oleic acid were observed. Embryoblast and trophoblast specific alterations in gene expression were found for ELOVLs and FADSs, key enzymes for FA elongation and desaturation. In conclusion, maternal diabetes mellitus alters embryonic FA metabolism differently in embryoblast and trophoblast, indicating a lineage-specific metabolic adaptive response.
The incidence of overweight and obesity has reached epidemic levels worldwide. Even more alarming is the increasing prevalence of metabolic diseases in younger children and adolescents. The rate of women with diabetes mellitus in child-bearing age is rising, too. According to the developmental origins of health and disease (DOHaD) paradigm, exposure to a hyperglycaemic environment in utero may programme physiology and metabolism permanently, with long-term consequences for offspring health. Experimental evidence indicates that programming of obesity does occur during early embryo development, a period where many women are unaware of pregnancy. To study effects of maternal diabetes mellitus on early embryo development, we induced a type I diabetes through alloxan treatment of female rabbits. In diabetic rabbits, the triglyceride and cholesterol concentrations were altered in serum and the cholesterol concentration in the uterine secretions was elevated. Lipid content of 6-day-old blastocysts was analysed after Oil Red staining and whole mount histochemistry or with Nile Red by fluorescence-activated cell sorting (FACS). Analysis by FACS revealed an approximately 2-fold increase in lipid droplets in blastocysts grown under diabetic conditions. The expression of genes important for lipid metabolism, such as fatty acid transport protein 4 (FATP4), fatty acid-binding protein 4 (FABP4), carnitine palmitoyltransferase 1 (CPT-1), and lipoprotein lipase (LPL), were determined by real-time PCR and showed distinct differences between diabetic and control blastocysts. Immunohistochemical staining of FABP4 was clearly increased in blastocysts grown under diabetic conditions and showed a cell lineage-specific distribution. Two transcription factors, peroxisome proliferator-activated receptor α (PPARα) and PPARγ, with key functions in lipid metabolism and adipogenic differentiation, were increased in blastocysts from diabetic rabbits. We show that maternal diabetes mellitus leads to alteration in lipid metabolism and to triglyceride accumulation in blastocysts. Its long-lasting consequences (e.g. for adipose cell differentiation) need attention and further investigation.
Although social isolation (SI) has shown to impede health and well-being, there is little knowledge about regional factors affecting SI. While urban life may hinder close contact with neighbors, advance in public transportation can make contact with friends and relatives easier. This study examined how the two aspects of urbanization affect SI among older adults when ADL declines. Data came from the National Survey of Japanese Elderly, a nationwide longitudinal study of Japanese older adults aged 60 and older. We analyzed 3132 respondents who lived in 192 municipalities (regions) and responded to 2-5 waves' interviews between 1996 and 2012, through hierarchical generalized linear models (threelevel model). SI was defined as having less contact than once a week with anyone outside the household. Regional level explanatory variables were "close-knit neighborhood" represented as median number of neighbors with whom one has close contact among respondents in the region, and availability of public transportation assessed by interviewers. Key individual time-varying or baseline attributes included gender, age, ADL/IADL, family/financial status, and number of close neighbors. Results showed that living in regions with close-knit neighborhood lowered probability of SI even after controlling for the individual characteristics, while availability of public transportation did not. Functional decline increased the probability of SI, but this negative impact was buffered by living in regions with higher availability of public transportation. Our findings indicate that urbanization does not necessarily promote SI, and that various resources are required to prevent SI according to phases of functional decline in later life. Recently South Koreans over the age of 65 committed suicide at a highest rate among the OECD countries. Therefore, there is a growing interest in early detection of depressive symptoms and other mental health problems in community settings. In order to analyze the factors influencing the competency of care providers regarding mental health issues, 324 family caregivers and 291 service providers working in facilities for elderly were surveyed using a structured questionnaire in 2016 in three cities in Korea. The average score for understanding mental health of older people was 3.29(5-point scale). Service providers had slightly higher score than the family caregivers. Family members were more reluctant than service providers towards seeking professional help for mental issues. However, service providers had more negative perception about current mental health service delivery system. Implications for improving the accessibility to early detection and prevention of mental health problems are discussed. Older adults comprise 7% of the Mongolian population and it is projected that they will account for 25% by 2050. Health care for older adults was greatly impacted by Mongolia's transition from a centrally planned to a free market economy. In 1998, the government established universal health insurance centralize...
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