MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways

The MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease

Maternal high-fat diet and offspring expression levels of vitamin K-dependent proteins

Studies suggest that bone growth and development and susceptibility to vascular disease in later life are influenced by maternal nutrition during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including osteocalcin, matrix Gla protein, periostin, and growth-arrest specific- protein 6, in both bone and vascular development. We have examined whether there are alterations in these VKDPs in bone and vascular tissue from offspring of mothers subjected to a nutritional challenge: a high-fat diet during pregnancy and postnatally, using 6-week-old mouse offspring. Bone site-specific and sex-specific differences across femoral and vertebral bone in male and female offspring were observed. Overall a high-fat maternal diet and offspring diet exacerbated the bone changes observed. Sex-specific differences and tissue-specific differences were observed in VKDP levels in aorta tissue from high-fat diet-fed female offspring from high-fat diet-fed mothers displaying increased levels of Gas6 and Ggcx compared with those of female controls. In contrast, differences were seen in VKDP levels in femoral bone of female offspring with lower expression levels of Mgp in offspring of mothers fed a high-fat diet compared with those of controls. We observed a significant correlation in Mgp expression levels within the femur to measures of bone structure of the femur and vertebra, particularly in the male offspring cohort. In summary, the current study has highlighted the importance of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure

Expression of agouti-related peptide, neuropeptide Y, pro-opiomelanocortin and the leptin receptor isoforms in fetal mouse brain from pregnant dams on a protein-restricted diet

Expression of agouti-related peptide, neuropeptide Y, pro-opiomelanocortin and leptin receptor isoforms were found in fetal mouse brain at embryonic day 12 (E12). Levels of expression for these genes were altered in brains of E12 fetuses from pregnant dams on a protein-restricted diet, suggesting that the fetal brain is responsive to changes in maternal nutrition prior to birth

Developmental exposure to bisphenol A leads to cardiometabolic dysfunction in adult mouse offspring

Bisphenol A (BPA) is a chemical compound that has adverse health outcomes in adults when exposed during the perinatal period. However, its effect on cardiovascular function remains to be elucidated. In this study, we examined the effects of daily administration of BPA to pregnant mice from gestational days 11 to 19 on cardiometabolic outcomes in the adult offspring. Prenatal BPA exposure resulted in altered growth trajectory and organ size, increase adiposity and impaired glucose homeostasis in male and female offspring. In addition, these BPA offspring exhibited raised systolic blood pressure, and in the males this was accompanied by impaired vascular tone. The aortas in females, but not in males, from the BPA group also showed reduced estrogen receptor gene expression. These results indicate that prenatal exposure to BPA increased susceptibility of the offspring to developing cardiovascular and metabolic dysfunction later in lif

Variation in stability of housekeeping genes in healthy and adhesion-related mesothelium

ObjectiveTo investigate the stability of various housekeeping genes (HKG) within healthy versus scarred peritoneal mesothelium. The use of HKG as internal controls for quantitative real-time polymerase chain reaction (qRT-PCR) studies is based on the assumption of their inherent stability. However, recent evidence suggests that this is not true for all HKG and that stability may be tissue specific and affected by certain pathologies.DesignPaired mesothelial (n = 10) and adhesion tissue samples (n = 10) were taken during laparoscopic surgery. The stability of 12 candidate reference genes in the mesothelial tissues were evaluated; these include ATP5b, SDHA, CYC1, 18S rRNA, RPL13A, ACTB, YWHAZ, TOP1, UBC, EIF4A2, GAPDH, and B2M.SettingHospital.Patient(s)Female patients undergoing laparoscopic gynecological surgery were recruited from the Princess Anne Hospital, United Kingdom.Intervention(s)Assessment of HKG expression stability using geNorm algorithm software.Main Outcome Measure(s)Stability measure (M) generated by geometric averaging of multiple target genes and mean pairwise variation of genes.Result(s)The most stable HKGs observed across both healthy and adhesion-related mesothelium were found to be ACTB, YWHAZ, and CYC1. ACTB had a higher expression in healthy mesothelium compared with in peritoneal adhesion tissue.Conclusion(s)This study indicates that ACTB, YWHAZ, and CYC1 are the appropriate internal controls for qRT-PCR analysis in mesothelial gene expression studies. Published discrepancies in gene expression studies using the mesothelium may therefore be due in part to inappropriate HKG selection<br/

A mismatched pre- and post-weaning diet has window of exposure- and sex-specific effects on energy homeostasis; adiposity and cardiovascular function in mice

Maternal diet during pregnancy and/or lactation plays a role in inducing the offspring metabolic phenotype. We examined the phenotypic outcome in offspring if they were fed a diet mismatched between pre- and postnatal life. Pregnant MF-1 mice were assigned to either control (C, 18% casein) or protein-restricted (PR, 9% casein) diet. PR dams were further sub-divided into those fed the PR diet throughout pregnancy (PRP) or both pregnancy and lactation (PRPL). Weaned offspring were then fed a high fat (HF, 45% Kcal fat) diet or standard chow (C, 21% Kcal fat) to adulthood. This generated six experimental groups based on dam/offspring dietary consumption: C/C, C/HF, PRP/C, PRP/HF, PRPL/C and PRPL/HF. Food intake and body weight were monitored and blood pressure was recorded by tail cuff plethysmography before animals were sacrificed. Hypothalamic tissues and fat depots were then collected for gene expression analysis by real time-PCR. Body weight and food intake was analyzed by mixed model analysis. All other data was analyzed by ANOVA with the appropriate post hoc test. HF offspring were heavier vs. C animals, regardless of maternal diet during pregnancy. However, PRPL/HF males were lighter vs. C/HF group, but were significantly fatter (p&lt;0.001). The increased adiposity observed in PRPL/HF males was not evident in the PRP/HF group. Daily energy intake was similar for all groups except for the PRP/HF males, whose intake was reduced by 20% vs. the PRP/C or C/HF groups (p&lt;0.001). PRP/HF males had reduced hypothalamic mRNA levels of genes involved in appetite regulation, namely neuropeptide Y (NPY) and the leptin receptor Ob-Rb, vs. PRP/C animals (p&lt;0.001 and p&lt;0.05, respectively). These PRP/HF males also had reduced expression of genes involved in thermogenesis, namely beta-3 adrenergic receptor and uncoupling protein 1, in the interscapulary brown adipose tissue vs. PRP/C animals (p&lt;0.05). These changes in gene expression were not observed in PRPL offspring. Systolic blood pressure in all PR offspring was greater by 16% and 10% in males and females, respectively, vs. C offspring (p&lt;0.05), and increased further (p&lt;0.05) by 15% and 7% in the HF male and female offspring, respectively. Our study shows that maternal protein restriction during pregnancy leads to sex-specific adaptive responses in male offspring, resulting in altered energy homeostasis following post-weaning HF-feeding. Extending maternal protein restriction to include the lactation period resulted in greater adiposity in the HF-fed male offspring. Nevertheless post-weaning HF-feeding exacerbated cardiovascular dysfunction in both male and female offspring, regardless of whether maternal protein restriction was imposed during pregnancy or both pregnancy and lactation

Skeletal bone morphology is resistant to the high amplitude seasonal leptin cycle in the Siberian hamster

Recent studies have suggested that the adipocyte-derived hormone, leptin, plays a role in the regulation of metabolism. Here, we tested this hypothesis in the seasonally breeding Siberian hamster, as this species exhibits profound seasonal changes in adiposity and circulating leptin concentrations driven by the annual photoperiodic cycle. Male hamsters were kept in either long (LD) or short (SD) photoperiods. Following exposure to short photoperiods for 8 weeks animals exhibited a significant weight-loss and a 16-fold reduction of serum leptin concentrations. At Week 9, animals in both photoperiods were infused with leptin or PBS via osmotic mini-pump for 14 days. Chronic leptin infusion mimicked LD-like concentrations in SD-housed animals and caused a further decline in body weight and adipose tissue. In LD-housed animals, leptin infusion resulted in a significant elevation of serum concentrations above natural LD-like levels, but had no discernable effect on body weight or overall adiposity. Both bending and compression characteristics and histomorphometric measurements of trabecular bone mass were unaltered by leptin treatment or photoperiod. Our data therefore show that despite a high natural amplitude cycle of leptin, this hormone has no apparent role in the regulation of bone metabolism, and therefore do not support recent propositions that this hormone is an important component in the metabolism of bone tissue