Background and objectiveMaternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring’s hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition.MethodsEight-week-old female Sprague–Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet.ResultsWith maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet.ConclusionMaternal overnutrition programs long-term epigenetic alterations in the offspring’s hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life.
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.
Small cell lung cancer (SCLC) has an extremely poor prognosis and methods of improving chemotherapeutic intervention are much sought after. A promising approach lies in inhibiting the tumour-associated enzyme, carbonic anhydrase IX (CA IX), which supports tumour cell survival. The aim of this study was to assess the potential of CA IX inhibition using 4-(3'-(3″,5″-dimethylphenyl)ureido)phenyl sulfamate (S4), for the treatment of human SCLC alone and in combination with cisplatin chemotherapy. Treating SCLC cell lines (DMS 79 and COR-L24) with 100 µM S4 reduced viability in vitro and enhanced cell death when combined with 7 µM cisplatin, most prominently under hypoxic conditions (0.1% O ). When either cell line was grown as a xenograft tumour in nude mice, intraperitoneal injection of 50 mg/kg S4 alone and in combination with 3 mg/kg cisplatin led to significantly reduced tumour growth. Combination therapy was superior to single agents and response was greatly accentuated when administering repeated doses of cisplatin in DMS 79 tumours. The mechanism of therapeutic response was investigated in vitro, where S4 treatment increased apoptosis under hypoxic conditions in both DMS 79 and COR-L24 cells. DMS 79 tumours receiving S4 in vivo also displayed increased apoptosis and necrosis. Combining S4 with cisplatin reduced both the area of hypoxia and CA IX-positive cells within tumours and increased necrosis, suggesting hypoxia-specific targeting. This study presents a novel, targeted approach to improving current SCLC therapy via inhibition of CA IX, which enhances apoptosis and significantly inhibits xenograft tumour growth when administered alone and in combination with cisplatin chemotherapy.
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