Nguyen, LT, Chen, H, Zaky, A, Pollock, C & Saad, S 2019, 'SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high-fat feeding.', The Journal of physiology, vol. 597, no. 2, pp. 467-480.View/Download from: UTS OPUS or Publisher's site
KEY POINTS:Maternal high-fat diet (MHF) consumption led to metabolic and liver disorders in male offspring, which are associated with reduced sirtuin (SIRT)1 expression and activity in the offspring liver SIRT1 overexpression in MHF offspring reduced their body weight and adiposity and normalized lipid metabolic markers in epididymal and retroperitoneal adipose tissues SIRT1 overexpression in MHF offspring improved glucose tolerance, as well as systemic and hepatic insulin sensitivity SIRT1 overexpression ameliorated MHF-induced lipogenesis, oxidative stress and fibrogenesis in the liver of offspring. ABSTRACT:Maternal obesity can increase the risk of metabolic disorders in the offspring. However, the underlying mechanism responsible for this is not clearly understood. Previous evidence implied that sirtuin (SIRT)1, a potent regulator of energy metabolism and stress responses, may play an important role. In the present study, we have shown, in C57BL/6 mice, that maternal high-fat diet (HFD) consumption can induce a pre-diabetic and non-alcoholic fatty liver disease phenotype in the offspring, associated with reduced SIRT1 expression in the hypothalamus, white adipose tissues (WAT) and liver. Importantly, the overexpression of SIRT1 in these offspring significantly attenuated the excessive accumulation of epididymal (Epi) white adipose tissue (WAT) and retroperitoneal (Rp)WAT (P < 0.001), glucose intolerance and insulin resistance (both P < 0.05) at weaning age. These changes were associated with the suppression of peroxisome proliferator-activated receptor gamma (PPAR)γ (P < 0.01), PPARγ-coactivator 1-alpha (P < 0.05) and sterol regulatory element-binding protein-1c in EpiWAT (P < 0.01), whereas there was increased expression of PPARγ in RpWAT (P < 0.05). In the liver, PPARγ mRNA expression, as well as Akt protein expression and activity, were increased (P < 0.05), whereas fatty acid synthase and carbohydrate response element binding protein were downregulated (P...
Nguyen, LT, Mak, CH, Chen, H, Zaky, AA, Wong, MG, Pollock, CA & Saad, S 2019, 'SIRT1 Attenuates Kidney Disorders in Male Offspring Due to Maternal High-Fat Diet.', Nutrients, vol. 11, no. 1.View/Download from: UTS OPUS or Publisher's site
Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers; however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury.
Li, G, Chan, YL, Nguyen, LT, Mak, C, Zaky, A, Anwer, AG, Shi, Y, Nguyen, T, Pollock, CA, Oliver, BG, Saad, S & Chen, H 2019, 'Impact of maternal e-cigarette vapor exposure on renal health in the offspring', ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 1452, no. 1, pp. 65-77.View/Download from: UTS OPUS or Publisher's site
Stangenberg, S, Nguyen, LT, Chan, YL, Zaky, A, Pollock, CA, Chen, H & Saad, S 2019, 'Maternal L-carnitine supplementation ameliorates renal underdevelopment and epigenetic changes in male mice offspring due to maternal smoking.', Clinical and experimental pharmacology & physiology, vol. 46, no. 2, pp. 183-193.View/Download from: UTS OPUS or Publisher's site
OBJECTIVES:Epidemiological and animal studies showed that L-carnitine (LC) supplementation can ameliorate oxidative stress-induced tissues damage. We have previously shown that maternal cigarette smoke exposure (SE) can increase renal oxidative stress in newborn offspring with postnatal kidney underdevelopment and renal dysfunction in adulthood, which were normalised by LC administration in the SE dams during pregnancy. Exposure to an adverse intrauterine environment may lead to alteration in the epigenome, a mechanism by which adverse prenatal conditions increase the susceptibility to chronic disease later in life. The current study aimed to determine whether maternal SE induces epigenetic changes in the offspring's kidney are associated with renal underdevelopment, and the protective effect of maternal LC supplementation. METHOD:Female Balb/c mice (7 weeks) were exposed to cigarette smoke (SE) or air (Sham) for 6 weeks prior to mating, during gestation and lactation. A subgroup of the SE dams received LC via drinking water (SE + LC, 1.5 mmol/L) throughout gestation and lactation. Male offspring were studied at postnatal day (P)1, P20, and 13 weeks. RESULTS:Maternal SE altered the expression of renal development markers glial cell line-derived neurotrophic factor and fibroblast growth factor 2, which were associated with increased renal global DNA methylation and DNA methyltransferase 1 mRNA expression at birth. These disorders were reversed by maternal LC administration. CONCLUSION:The effect of maternal SE on renal underdevelopment involves global epigenetic alterations from birth, which can be prevented by maternal LC supplementation.
Nguyen, LT, Chen, H, Mak, C, Zaky, A, Pollock, C & Saad, S 2018, 'SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption.', American journal of physiology. Endocrinology and metabolism, vol. 315, no. 2, pp. E196-E203.View/Download from: UTS OPUS or Publisher's site
Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow-fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high-fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined.
Wong, MG, The, NL & Glastras, S 2018, 'Maternal obesity and offspring risk of chronic kidney disease.', Nephrology (Carlton, Vic.), vol. 23 Suppl 4, pp. 84-87.View/Download from: UTS OPUS or Publisher's site
It is increasingly recognized that maternal obesity is implicated in developmental programming, contributing to the future risk of chronic disease development in offspring. The exact mechanisms of the role of maternal obesity in the development of chronic kidney disease in offspring remain unclear and animal models used are not without limitation. Human studies are limited by the effects of postnatal environmental conditions, which may have a direct impact on disease phenotype; and animal models are limited by use of species that differ significantly. This review will examine the most recent evidence from animal models on the impact of maternal factors during pregnancy/lactation on the future risk of chronic kidney disease development in offspring, emphasising the role of maternal obesity in exacerbating the deleterious effects of diet-induced obesity and/or diabetes on renal health.
Sukjamnong, S, Chan, YL, Zakarya, R, Nguyen, LT, Anwer, AG, Zaky, AA, Santiyanont, R, Oliver, BG, Goldys, E, Pollock, CA, Chen, H & Saad, S 2018, 'MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring.', Scientific reports, vol. 8, no. 1.View/Download from: UTS OPUS or Publisher's site
To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring.
Nguyen, LT, Chen, H, Pollock, C & Saad, S 2017, 'SIRT1 reduction is associated with sex-specific dysregulation of renal lipid metabolism and stress responses in offspring by maternal high-fat diet.', Scientific Reports, vol. 7, no. 1, pp. 1-13.View/Download from: UTS OPUS or Publisher's site
Rodent models of maternal obesity have been associated with kidney damage and dysfunction in offspring. However, the underlying mechanisms are yet to be elucidated. In this study, female rats were fed a high-fat diet (HFD) for 6 weeks prior to mating, throughout gestation and lactation; both male and female offspring were examined at weaning. Our results demonstrate that renal lipid deposition was increased in male offspring only, which is associated with reduced protein expression of Sirtuin (SIRT) 1, an essential regulator of lipid metabolism and stress response. Other components in its signalling network including phosphorylated 5'-AMP-activated protein kinase (pAMPKα), Forkhead box FOXO3a and Peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-alpha (PGC-1α) were also downregulated. By contrast, in female offspring, renal fat/lipid distribution was unchanged in coupling with normal SIRT1 regulation. Specific autophagy and antioxidant markers were suppressed in both sexes. On the other hand, fibronectin and Collagen type IV protein expression was significantly higher in the offspring born HFD-fed dams, particularly in the males. Collectively, these findings suggest that maternal HFD consumption can induce sex-specific changes in offspring kidney lipid metabolism and stress responses at early ages, which may underpin the risk of kidney diseases later in life.
Nguyen, LT, Saad, S, Tan, Y, Pollock, C & Chen, H 2017, 'Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus.', Journal of Molecular Endocrinology, vol. 59, no. 1, pp. 81-92.View/Download from: UTS OPUS or Publisher's site
Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.
Nguyen, LT, Chen, H, Pollock, CA & Saad, S 2016, 'Sirtuins-mediators of maternal obesity-induced complications in offspring?', FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 30, no. 4, pp. 1383-1390.View/Download from: UTS OPUS or Publisher's site
Obesity is a complex metabolic disease, attributed to diverse and interactive genetic and environmental factors. The associated health consequences of obesity are pleiotropic, with individuals being more susceptible to chronic diseases such as type 2 diabetes mellitus, hypertension, and lipotoxicity-related chronic diseases. The contribution of maternal obesity to the offspring's predisposition to both obesity and its complications is increasingly recognized. Understanding the mechanisms underlying these "transmissible" effects is critical to develop therapeutic interventions to reduce the risk for "programmed" obesity. Sirtuins (SIRTs), particularly SIRT1 and SIRT3, are NAD(+)-dependent deacetylases that regulate metabolic balance and stress responses in both central and peripheral tissues, of which dysregulation is a well-established mediator for the development and effects of obesity. Nevertheless, their implication in the transmissible effects of maternal obesity across generations remains largely elusive. In this review, we examine multiple pathways and systems that are likely to mediate such effects, with particular emphasis on the role of SIRTs.-Nguyen, L. T., Chen, H., Pollock, C. A., Saad, S. Sirtuins-mediators of maternal obesity-induced complications in offspring?
Chen, H, Chan, YL, Nguyen, LT, Mao, Y, de Rosa, A, Beh, IT, Chee, C, Oliver, B, Herok, G, Saad, S & Gorrie, C 2016, 'Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, vol. 43, no. 11, pp. 1107-1114.View/Download from: UTS OPUS or Publisher's site
Stangenberg, S, Nguyen, LT, Chen, H, Al-Odat, I, Killingsworth, MC, Gosnell, ME, Anwer, AG, Goldys, EM, Pollock, CA & Saad, S 2015, 'Oxidative stress, mitochondrial perturbations and fetal programming of renal disease induced by maternal smoking', INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, vol. 64, pp. 81-90.View/Download from: UTS OPUS or Publisher's site
Van-Minh, L, Wang, J-J, Yuan, M, The-Long, N, Yin, G-F, Zheng, Y-H, Shi, W-B, Lang, M-D, Xu, L-M & Liu, J-W 2015, 'An investigation of antitumor efficiency of novel sustained and targeted 5-fluorouracil nanoparticles', EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 92, pp. 882-889.View/Download from: UTS OPUS or Publisher's site
Nguyen, LT, Stangenberg, S, Chen, H, Al-Odat, I, Chan, YL, Gosnell, ME, Anwer, AG, Goldys, EM, Pollock, CA & Saad, S 2015, 'L-Carnitine reverses maternal cigarette smoke exposure-induced renal oxidative stress and mitochondrial dysfunction in mouse offspring.', American journal of physiology. Renal physiology, vol. 308, no. 7, pp. F689-F696.View/Download from: UTS OPUS or Publisher's site
Maternal smoking is associated with metabolic disorders, renal underdevelopment, and a predisposition to chronic kidney disease in offspring, yet the underlying mechanisms are unclear. By exposing female Balb/c mice to cigarette smoke for 6 wk premating and during gestation and lactation, we showed that maternal smoke exposure induced glucose intolerance, renal underdevelopment, inflammation, and albuminuria in male offspring. This was associated with increased renal oxidative stress and mitochondrial dysfunction at birth and in adulthood. Importantly, we demonstrated that dietary supplementation of l-carnitine, an amino acid shown to increase antioxidant defenses and mitochondrial function in numerous diseases, in smoke-exposed mothers during pregnancy and lactation significantly reversed the detrimental maternal impacts on kidney pathology in these male offspring. It increased SOD2 and glutathione peroxidase 1, reduced ROS accumulation, and normalized levels of mitochondrial preprotein translocases of the outer membrane, and oxidative phosphorylation complexes I-V in the kidneys of mouse progeny after intrauterine cigarette smoke exposure. These findings support the hypothesis that oxidative stress and mitochondrial dysfunction are closely linked to the adverse effects of maternal smoking on male offspring renal pathology. The results of our study suggest that l-carnitine administration in cigarette smoke-exposed mothers mitigates these deleterious renal consequences.