Coenzyme Q10 Prevents Insulin Signaling Dysregulation and Inflammation Prior to Development of Insulin Resistance in Male Offspring of a Rat Model of Poor Maternal Nutrition and Accelerated Postnatal Growth.

Low birth weight and rapid postnatal growth increases the risk of developing insulin resistance and type 2 diabetes in later life. However, underlying mechanisms and potential intervention strategies are poorly defined. Here we demonstrate that male Wistar rats exposed to a low-protein diet in utero that had a low birth weight but then underwent postnatal catch-up growth (recuperated offspring) had reductions in the insulin signaling proteins p110-β (13% ± 6% of controls [P < .001]) and insulin receptor substrate-1 (39% ± 10% of controls [P < .05]) in adipose tissue. These changes were not accompanied by any change in expression of the corresponding mRNAs, suggesting posttranscriptional regulation. Recuperated animals displayed evidence of a proinflammatory phenotype of their adipose tissue with increased IL-6 (139% ± 8% [P < .05]) and IL1-β (154% ± 16% [P < .05]) that may contribute to the insulin signaling protein dysregulation. Postweaning dietary supplementation of recuperated animals with coenzyme Q (CoQ10) (1 mg/kg of body weight per day) prevented the programmed reduction in insulin receptor substrate-1 and p110-β and the programmed increased in IL-6. These findings suggest that postweaning CoQ10 supplementation has antiinflammatory properties and can prevent programmed changes in insulin-signaling protein expression. We conclude that CoQ10 supplementation represents an attractive intervention strategy to prevent the development of insulin resistance that results from suboptimal in utero nutrition.This work was supported by The British Heart Foundation [PG/09/037/27387, FS/09/029/27902]; Medical Research Council [MC UU 12012/4] and Diabetes UK [12/0004508]. SEO is a member of the MRC Metabolic Diseases Unit. IPH is supported by the Department of Health’s NIHR Biomedical Research Centres funding scheme at UCLH/UCL.This is the author accepted manuscript. The final version is available from the Endocrine Society via http://dx.doi.org/10.1210/en.2015-142

Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth.

BACKGROUND: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. OBJECTIVES: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. DESIGN: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. RESULTS: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). CONCLUSIONS: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.This work was supported by The British Heart Foundation [PG/09/037/27387, FS/09/029/27902]; and The Medical Research Council [MC_UU_12012/4]. Serum analysis was performed by The Wellcome Trust Supported Cambridge Mouse Laboratory, UK. SEO is a member of the MRC Metabolic Diseases Unit. IPH is supported by the Department of Health’s NIHR Biomedical Research Centers funding scheme at UCLH/UCL.This is the final version of the article. It first appeared from the American Society for Nutrition via http://dx.doi.org/10.3945/ajcn.115.11983

Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice

We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110 beta, the catalytic subunit of PI3K (P &lt;0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKC zeta expression (P &lt;0.01; P &lt;0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams (P &lt;0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice

The effect of tamoxifen on the ovarian follicles and notch signaling pathway

Tamoksifen, seçici östrojen reseptör modülatörlerinden biridir. Günümüzde menapoz öncesi ve sonrası yüksek risk grubunda yer alan kadınlarda meme kanserinin önlenmesinde ve meme kanserli hastaların tedavisinde yaygın olarak kullanılmaktadır. Tamoksifenin menapoz öncesi kadınlarda kullanılması, onların fertilitelerini etkileyebilir. Sunulan tezin I. amacı; tamoksifenin puberta döneminde ovaryum follikül atrezisi ya da proliferasyonu üzerine etkilerini incelemektir. II. amacı; tamoksifenin ovaryum üzerine yapacağı etkilerin mekanizmasında Notch sinyal yolağının önemli bir rolünün olup/ olmadığını belirlemektir. Bu amaçlarla hayvanlar; kontrol grubu (n: 20) , tamoksifenin eritildiği taşıyıcı solüsyonun enjekte edildiği (n: 20) , 0.5mg/fare/gün (n: 20) , 1.5mg/fare/gün (n: 20) tamoksifen enjekte edilen olmak üzere 4 gruba ayrıldı ve 5 gün süre ile subkutan enjeksiyon yapıldı. Deney sonrasında hayvanların ovaryum ağırlığı ve canlı ağırlık kazancı değerlendirildi. Ovaryum kesitlerine genel yapı ve follikül sayımı için; üçlü boyama, apoptozisi belirlemek için; Tunel yöntemi uygulandı. Ayrıca hücre proliferasyonu için; Ki 67, Notch 2 ve Jagget 1 ekspresyonunu belirlemek için; immunohistokimyasal boyama yöntemi uygulandı. Çalışmada, hayvan grupları arasında canlı ağırlık kazancı ve ovaryum ağırlığı bakımından istatistiksel olarak farklılık gözlenmedi. Tamoksifen uygulanan grupların ovaryumunda, primordiyal folliküllerin sayısının kontrol grubuna göre yüksek, antral follikül sayısının ve korpus luteum sayısının ise az olduğu belirlendi. Bununla birlikte tamoksifenin folliküllerde atreziyi arttırdığı, hücre proliferasyon oranını azalttığı gözlendi. Tamoksifenin granuloza hücrelerinde Notch 2 ekspresyonunu arttırdığı; fakat Jagget 1 ekspresyonu üzerine etkili olmadığı belirlendi. Sonuçta uygulanan tamoksifen dozlarının primordiyal follikül havuzunu etkilemediği; fakat follikül gelişimini baskıladığı gözlenmiştir. Ayrıca tamoksifenin folliküller üzerine yaptığı etkilerde Notch sinyal yolağının rolü olabilir.Tamoxifen is a selective estrogen receptor modulator. Currently, tamoxifen is being used for the treatment of breast cancer and as a prophylactic agent in healthy women with high-risk for breast cancer. Tamoxifen use in premenopausal women may affect their fertility. The first aim of this study is to investigate the effects of tamoxifen on ovary follicle atresia or follicle proliferation in puberty. The second aim of this study is to determine if the Notch signaling patway serves a role in mediating the effects of tamoxifen on the ovary. For these purposes, animals were divided to 4 groups: No injection group (n: 20) , vehicle injected group (n: 20) , 0.5 mg/mouse/day tamoxifen group (n: 20) , and 1.5 mg/mouse/day tamoxifen group (n: 20) . Mice were given daily s.c. injections for 5 days. At the end of the experiment, ovarian weights and body weights gain were determined. Ovarian sections were stained with triple to examine the general structure of the ovary and number of follicles. Tunel assay was used for apoptosis. İmmunohistochemical analyses were performed on sections to determine the expressions of Notch 2 and Jagget 1 and Ki 67 for cell proliferation. In the present study, there were no significant differences on weight gain and ovarian weight between control groups and tamoxifen-treated groups. The number of primordial follicles was higher while the number of antral follicle and corpus luteum was lower in the tamoxifen-treated groups than in the control groups. In addition, tamoxifen treatment increased follicular atresia and reduced cell proliferation. Tamoxifen caused an increase in Notch 2 expression in the granulosa cells while it had no effect on Jagged 1 expression. As a result, tamoxifen did not change primordial follicles pool but suppressed the follicular development. However, the Notch signaling pathway may be involved in the observed effect of tamoxifen on follicles