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  • ryanodine manufacturer br Maternal obesity high fat feeding

    2018-10-29


    Maternal obesity/high fat feeding The prevalence of maternal obesity is increasing at an alarming rate [21], however, the consequences for the health of the offspring in later life is poorly understood compared with that of fetal undernutrition and fetal growth restriction. In various experimental models including sheep and rodents, offspring of obese mothers, or mothers exposed to a high-fat diet generally exhibit increased birth weight and fat mass [22–28]. Other reports showed no changes in birth weight [29–37] possibly due to differences of the animal models and experimental designs. Furthermore the severity, length and timing of maternal high-fat feeding and the postnatal growth profile of the offspring may also contribute to the interpretation of offspring health outcomes. In later life, offspring of obese or high-fat fed mothers are more susceptible to developing non-alcoholic fatty liver disease [30,38], insulin resistance [39,40], glucose intolerance [24,25,39,40], obesity [25,39,40], hyperphagia [25], hypertension [25,32,41] and cardiovascular impairments [25,32,41]. Tissue-specific alterations in gene expression and organ development in early life, induced by obesity related maternal factors that alter the gestational milieu, likely have impact on tissue function throughout the life span. Fetal nutrient supply during gestation is dependent on both maternal nutritional status and the transfer of those nutrients across the placenta. Obesity and high-fat diet are often associated with elevated circulating lipids, inflammation and insulin resistance. During pregnancy, obesity and high-fat diet result in significantly increased lipid transfer across the placenta and exposure of the fetus to lipids at an earlier stage of gestation than normal [42]. The early and increased lipid exposure is likely augmented by elevated gene and protein expression of the placental fatty ryanodine manufacturer transporters (FATP1, FATP4 and CD36), which has been reported in obese pregnant ewes at 75 and 135d of gestation (term=145d)[42]. Indeed, elevated free fatty acids, triglycerides and cholesterol were also observed in the placenta and in the plasma of the fetus [28]. Lipid species are able to activate cell signaling pathways and act as ligands for nuclear receptors. Therefore, increased circulating lipids in the fetal circulation has the potential to alter gene expression during development and may play a role in the cellular signaling processes responsible for increased susceptibility of later disease. Elevated circulating lipids are associated with widespread inflammation in obese conditions [43]. In obese pregnant ewes, elevated lipids in the placenta was associated with activation of inflammatory signaling pathways of c-Jun N-terminal kinase (JNK/c-jun) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) via activation of the Toll-like receptor 4 (TLR4) of which free fatty acids are known ligands [28]. Activation of inflammatory signaling was also associated with increased levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8 and IL-18 mRNA in the placenta [28]. Importantly, similar findings were reported in obese human mothers along with macrophage accumulation in the placenta [23]. It is likely that the inflammatory factors and resulting oxidative stress cues within the placenta of obese mothers can be transferred to the fetus and activate/repress important signaling events resulting in abnormal development [23,28]. However, to date few studies have investigated the impact of maternal or placental inflammation on offspring development and later health. One study showed that inflammation during pregnancy had a significant adverse impact on the development of the fetal brain and nervous system [44], which could contribute to behavioral and cognitive irregularities and conditions such as autism, schizophrenia, cerebral palsy, blindness and mental retardation. It is, therefore, likely that a maternal obesity-induced inflammatory environment would contribute to maladaptive programming events in other fetal organs/tissues. Indeed, inflammation has been shown to impair myogenic differentiation and skeletal muscle development [45,46], while promoting adipogenesis possibly through alterations in NF-κB signaling [26,47]. Therefore, maternal-fetal inflammation represents an important mechanism likely responsible for alterations in the developmental gene program and abnormal growth leading to increased disease susceptibility later in life. The impact of maternal obesity/high fat diet to offspring during development and consequences in later life are summarized in Fig. 1.