Effects of maternal diet-induced obesity on metabolic disorders and age-associated miRNA expression in the liver of male mouse offspring

Objective: This study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA. Methods: A mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring. Results: Body weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 ± 0.8 g versus 10.4 ± 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 ± 2.1 g versus 12.9 ± 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgfβ1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPKα, total AMPKα and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (−3p: 7.34 ± 1.35 versus 1.39 ± 0.50, p < 0.0001 and −5p: 4.66 ± 1.16 versus 1.63 ± 0.65, p < 0.05). Conclusion: Our findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny

Stakeholder Salience for Small Businesses : A Social Proximity Perspective

This paper advances stakeholder salience theory from the viewpoint of small businesses. It is argued that the stakeholder salience process for small businesses is influenced by their local embeddedness, captured by the idea of social proximity, and characterised by multiple relationships that the owner-manager and stakeholders share beyond the business context. It is further stated that the ethics of care is a valuable ethical lens through which to understand social proximity in small businesses. The contribution of the study conceptualises how the perceived social proximity between local stakeholders and small business owner-managers influences managerial considerations of the legitimacy, power and urgency of stakeholders and their claims. Specifically, the paradoxical nature of close relationships in the salience process is acknowledged and discussed.Peer reviewe

Implications of market integration for cardiovascular and metabolic health among an indigenous Amazonian Ecuadorian population

BackgroundMarket integration (MI), the suite of social and cultural changes that occur with economic development, has been associated with negative health outcomes such as cardiovascular disease; however, key questions remain about how this transition manifests at the local level.AimThe present paper investigates the effects of MI on health among Shuar, an indigenous lowland Ecuadorian population, with the goal of better understanding the mechanisms responsible for this health transition.Subjects and methodsThis study examines associations between measures of MI and several dimensions of cardiovascular and metabolic health (fasting glucose, lipids [LDL, HDL and total cholesterol; triglycerides] and blood pressure) among 348 adults.ResultsOverall, Shuar males and females have relatively favourable cardiovascular and metabolic health. Shuar who live closer to town have higher total (p &lt; 0.001) and HDL cholesterol (p &lt; 0.001), while Shuar in more remote regions have higher diastolic blood pressure (p = 0.007). HDL cholesterol is positively associated with consumption of market foods (r = 0.140; p = 0.045) and ownership of consumer products (r = 0.184; p = 0.029).ConclusionsThis study provides evidence that MI among Shuar is not a uniformly negative process but instead produces complex cardiovascular and metabolic health outcomes

Maternal overnutrition programs cardiac dysfunction independently of post-natal diet in mice

PURPOSE Gestational exposure to maternal obesity increases the risk of cardiovascular disease in the offspring. Exposure to overnutrition during fetal life is likely to be followed by continued exposure to the same calorie-rich environment post-natally. The aim of this project was to characterize the consequences of combined exposure to a maternal and post-natal obesogenic diet on offspring cardiac structure and function. METHODS A well-established mouse model of maternal diet-induced obesity where C57bl/6 dams are fed a high fat/high simple carbohydrate diet during pre-gestation, gestation and lactation was used. Male offspring from control (C-) and obese (O-) were assigned at weaning to either a control (-C) or obesogenic diet (-O), generating 4 experimental groups (CC, CO, OC and OO). Metabolic profile, cardiac structure and function, gene expression, and blood pressure were assessed in male offspring at 8 weeks of age. RESULTS Dams fed the obesogenic diet were significantly heavier on the day of mating (p<0.0001), and remained heavier throughout pregnancy and at weaning compared to controls. Young adult (8 weeks) offspring exposed to maternal overnutrition had heavier hearts (17%) than control mice (effect of maternal diet p=0.005). A post-weaning obesogenic diet also increased heart weight (effect of offspring diet p=0.019). Circulating levels of insulin and leptin were increased by feeding the obesogenic diet, and further elevated by the maternal exposure. Mice born to overnourished mothers developed pathological ventricular remodelling associated with re-expression of cardiac fetal genes (Nppa, Myh7, Myh7:Myh6 ratio), interventricular septum thickening (p=0.0004), increased left ventricular area (p=0.02), cardiac systolic dysfunction with reduced ejection fraction and fractional shortening. Most importantly, up-regulation of genes involved in cardiac contraction was observed in fetuses from obese dams as early as in utero. CONCLUSIONS Maternal overnutrition programs adverse cardiac remodelling and dysfunction in adult male offspring. These findings suggest that a maternal caloric-rich uterine environment is a critical determinant of cardiovascular disease risk in the next generation, and is as detrimental as current obesity

Maternal but not fetoplacental health can be improved by metformin in a murine diet‐induced model of maternal obesity and glucose intolerance

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg/kg/day) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669±568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass, and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (p<0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7±125.4 nmol/g in the placenta and 2063±2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk versus benefits that are weighed in obstetric medical treatments