Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis.
Abstract In early life, over-nutrition may increase the risk of insulin resistance in the adult stage. Adiponectin and its receptor may play a key role in this process. This study aimed to identify the effect of a high-fat (HF) maternal diet on metabolic parameters and muscle adiponectin signaling in young adult offspring. We found that offspring born to dams fed HF chow (HF; 31% of calories from fat) had elevated body and adipose tissue weight and higher serum glucose levels after glucose challenge at three weeks (W3) and eight weeks (W8) of age. Offspring exposed to a HF diet also had higher serum adiponectin levels at W3 compared to controls. However, adiponectin levels were significantly decreased compared to controls by W8. Adiponectin receptor 1?mRNA expression in skeletal muscle was decreased in the HF group at W3 and W8, and there was no difference between the two groups in adiponectin receptor 2 expression. Furthermore, glucose transporter 4?mRNA and protein expression was decreased in the skeletal muscle of the HF group at W3 and W8. Our results suggest that a HF maternal diet decreases adiponectin receptor 1 expression in the offspring, which could contribute to reduced sensitivity to adiponectin and to adverse nutritional programing outcomes.
Single-stranded guanine-rich sequences fold into compact G-quadruplexes. Although G-triplexes have been proposed and demonstrated as intermediates in the folding of G-quadruplexes, there is still a debate on their folding pathways. In this work, we employed magnetic tweezers to investigate the folding kinetics of single human telomeric G-quadruplexes in 100 mM Na(+) buffer. The results are consistent with a model in which the G-triplex is an in-pathway intermediate in the folding of the G-quadruplex. By finely tuning the force exerted on the G-quadruplex, we observed reversible transitions from the G-quadruplex to the G-triplex as well as from the G-triplex to the unfolded coil when the force was increased from 26 to 39 pN. The energy landscape derived from the probability distribution shows clearly that the G-quadruplex goes through an intermediate when it is unfolded, and vice versa.
Elevated glucocorticoid (GC) activity may be involved in the development of the metabolic syndrome. Tissue GC exposure is determined by the tissue-specific GC-activating enzyme 11?-hydroxysteriod dehydrogenase type 1 (11?-HSD1) and the GC-inactivating enzyme 5?-reductase type 1 (5?R1), as well as 5?-reductase (5?R). Our aim was to study the effects of neonatal overfeeding induced by small litter rearing on the expression of GC-regulating enzymes in adipose tissue and/or liver and on obesity-related metabolic disturbances during development. Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litters, SL) or ten (normal litters, NL) on postnatal day 3 and then given standard chow from postnatal week 3 onward (W3). Small litter rearing induced obesity, hyperinsulinemia, and higher circulating corticosterone in adults. 11?-HSD1 expression and enzyme activity in retroperitoneal, but not in epididymal, adipose tissue increased with postnatal time and peaked at W5/W6 in both groups before declining. From W8, 11?-HSD1 expression and enzyme activity levels in retroperitoneal fat persisted at significantly higher levels in SL compared to NL rats. Hepatic 11?-HSD1 enzyme activity in SL rats was elevated from W3 to W16 compared to NL rats. Hepatic 5?R1 and 5?R expression was higher in SL compared to NL rats after weaning until W6, whereupon expression decreased in the SL rats and remained similar to that in NL rats. In conclusion, small litter rearing in rats induced peripheral tissue-specific alterations in 11?-HSD1 expression and activity and 5?R1 and 5?R expression during puberty, which could contribute to elevated tissue-specific GC exposure and aggravate the development of metabolic dysregulation in adults.
Activation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue results in the production of excess tissue glucocorticoids and the induction of adiposity and visceral obesity in particular. Androgens may affect body fat distribution by regulating the local metabolism of cortisol.
We report on the fabrication of a subnanometer-thick epitaxial PbS film on polydiacetylene (PDA) substrate. The film is formed by cation-absorption in PbCl2 solution followed by sulfidation in mixed H2S/N2 gas, exhibiting a flat and smooth surface morphology. The strong adsorbate-surface interaction between the lead hydrolysis complexes and the carboxyl headgroups on the surface of PDA accounts for such a growth mode. We further demonstrate that such an ultrathin film can be used as a buffer layer for both homo- and heteroepitaxial growth of sulfide films. The X-ray and electron diffraction results reveal that the (001) planes of PbS are parallel to the surface of PDA and the (110) planes of PbS are parallel to the (110) planes of PDA.
Structural properties of single lambda DNA treated with anti-cancer drug cisplatin were studied with magnetic tweezers and AFM. Under the effect of low-concentration cisplatin, the DNA became more flexible, with the persistence length decreased significantly from approximately 52 to 15 nm. At a high drug concentration, a DNA condensation phenomenon was observed. Based on experimental results from both single-molecule and AFM studies, we propose a model to explain this kind of DNA condensation by cisplatin: first, di-adducts induce local distortions of DNA. Next, micro-loops of approximately 20 nm appear through distant crosslinks. Then, large aggregates are formed through further crosslinks. Finally, DNA is condensed into a compact globule. Experiments with Pt(dach)Cl(2) indicate that oxaliplatin may modify the DNA structures in the same way as cisplatin. The observed loop structure formation of DNA may be an important feature of the effect of platinum anti-cancer drugs that are analogous to cisplatin in structure.
We report observations of in vitro DNA compaction into toroids in the absence of any condensing agent. The DNA toroid formation is induced by geometry confinement from microdroplets on mica surfaces. With AFM imaging we show that the confined DNA molecules may take the form of random coils or semiordered folded loops with large microdroplets, while they readily take the form of compact and ordered toroids when the microdroplet sizes are small enough. To better understand these phenomena, we carried out coarse-grained Brownian dynamics simulation, obtaining results that were in good agreement with the experimental observations. The simulation reveals that the toroid formation is sensitive to not only the microdroplet size, but also the DNA stiffness.
Early life nutrition is important in the regulation of metabolism in adulthood. We studied the effects of different fatty acid composition diets on adiposity measures, glucose tolerance, and peripheral glucocorticoid (GC) metabolism in overfed neonatal rats. Rat litters were adjusted to a litter size of three (small litters (SLs)) or ten (normal litters (NLs)) on postnatal day 3 to induce overfeeding or normal feeding respectively. After weaning, SL and NL rats were fed a ?6 polyunsaturated fatty acid (PUFA) diet (14% calories as fat, soybean oil) or high-saturated fatty acid (high-fat; 31% calories as fat, lard) diet until postnatal week 16 respectively. SL rats were also divided into the third group fed a ?3 PUFA diet (14% calories as fat, fish oil). A high-fat diet induced earlier and/or more pronounced weight gain, hyperphagia, glucose intolerance, and hyperlipidemia in SL rats compared with NL rats. In addition, a high-fat diet increased 11?-hsd1 (Hsd11b1) mRNA expression and activity in the retroperitoneal adipose tissue of both litter groups compared with standard chow counterparts, whereas high-fat feeding increased hepatic 11?-hsd1 mRNA expression and activity only in SL rats. SL and a high-fat diet exhibited significant interactions in both retroperitoneal adipose tissue and hepatic 11?-HSD1 activity. Dietary ?3 PUFA offered protection against glucose intolerance and elevated GC exposure in the retroperitoneal adipose tissue and liver of SL rats. Taken together, the results suggest that dietary fatty acid composition in the post-sucking period may interact with neonatal feeding and codetermine metabolic alterations in adulthood.
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