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AbstractObjective: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose.Research Methods and Procedures: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice.Results: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern.Discussion: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

Thirty-two pregnant Long-Evans rats were divided into 10 groups of 3 or 4 pregnant rats, and each rat was given a single dose of 4 ml ethanol/kg (20 ml/kg of a 20% solution) between d 6 and 15 of gestation. An 11th group of 50 pregnant rats received distilled water and served as controls. Offspring body weights were decreased in groups of rats given ethanol as compared to controls (3.0-3.6 g, versus 3.9 g for controls). Total litter weight was decreased in dams given ethanol on d 6. Skeletal variants were seen in 13-78% of the offspring given ethanol, compared to 0.6% of the controls. Variations may be considered as additional signs of embryotoxicity. Malformations such as hydronephrosis, pelvic kidney, microcephalus, cranioschisis, and microphthalmia occurred in 72-100% of the ethanol treated offspring, as compared to 12% of controls. Hydronephrosis was most frequent on d 9 or 14, pelvic kidney on d 8 and 11, and microphthalmia from d 10-12. Cranioschisis was maximal on d 7, 11, and 15, and microcephalic offspring were most frequently born to dams given ethanol on d 7 or 14. Skeletal defects were usually single entities, while soft-tissue anomalies occurred in a consistent pattern. These results suggest that ethanol is a stage-specific teratogen in the rat at comparable exposure levels attained by many humans.

Long-Evans and Sprague-Dawley rats show differential behavioral responses to cocaethylene, a metabolite derived from the simultaneous ingestion of ethanol and cocaine. Such differences may also be manifested when these outbred strains are exposed to ethanol and cocaine. To test this hypothesis, both strains were fed an ethanol-diet (8.7% v/v) in conjunction with cocaine (15 mg/kg) injections for 15 days. The following parameters were evaluated: (a) ethanol consumption, (b) cocaine-induced behavioral activity, (c) blood ethanol levels, (d) blood, liver, or brain cocaine and cocaethylene levels, and (e) liver catalase and esterase activity. We found that Long-Evans rats drank significantly more of the ethanol diet relative to the Sprague-Dawley line during the first few days of the test session. This rat phenotype also differed significantly from the Sprague-Dawley line in terms of behavioral activity after cocaine administration. Blood ethanol levels did not differ between strains. Similarly, we failed to detect strain-dependent differences in blood, liver, or brain cocaine levels as measured by gas chromatography/mass spectrometry. Cocaethylene levels, however, were higher in blood and brain of Long-Evans relative to Sprague-Dawley cohorts. Although the ethanol-cocaine regimen produced a marked suppression of catalase and esterase activity compared with control-fed rats, this suppression was roughly equivalent in both rat phenotypes. These data are discussed in the context of genotypic background and vulnerability to polysubstance abuse.

AbstractThe present study was undertaken to assess the influences of chronic maternal ethanol consumption, prior to and during gestation, on the development of synaptic plasma membranes (SPMs) and on the synthesis of SPM glycoproteins in offspring. Comparisons were made between animals whose mothers were pair‐fed a control or 6.6% (v/v) ethanol liquid diet in which protein accounted for either 18% (original) (C & E) or 21% (revised) (*C & *E) of the calories. In addition, groups of pups that were either cross‐fostered (*C & *E) with chow‐fed surrogate mothers or reverse cross‐fostered (offspring of chow‐fed mothers with *C & *E mothers) were examined. Ethanol and matched (same dietary group) control pups had comparable brain and body weights, brain protein content, and yield of SPM proteins during the 10–24 day age period examined. However, the yield of SPM proteins from ethanol and control offspring of and/or reared by the three groups of rat mothers that received the *E and *C liquid diets was greater than that of the offspring of rats that were fed the original diets. This suggests that the original diets were not nutritionally adequate for pregnant rats. Despite the fact that the content of SPM proteins was comparable in ethanol and matched control pups, the offspring of ethanol‐treated rats had an abnormal distribution of [3H]‐or [14C]‐fucose‐derived radioactivity among SPM glycoproteins. The SPM abnormalities were most severe in the non‐cross‐fostered offspring of E rats. No SPM glycoprotein abnormalities were found in the reverse cross‐fostered group. The results of the present study demonstrate that chronic maternal ethanol consumption prior to parturition has a severe effect on the synthesis of SPM glycoproteins in developing offspring without affecting the content of SPMs per se. It also demonstrates the importance of optimizing the composition of liquid diets used to feed pregnant rats.

Background: Alcohol-related brain degeneration is linked to cognitive-motor deficits and impaired signaling through insulin/insulin-like growth factor type 1 (IGF-1)-Akt pathways that regulate cell survival, plasticity, metabolism, and homeostasis. In addition, ethanol inhibits Aspartyl-asparaginyl-β-hydroxylase (ASPH), a downstream target of insulin/IGF-1-Akt signaling and an activator of Notch networks. Previous studies have suggested that early treatment with insulin sensitizers or dietary soy could reduce or prevent the long-term adverse effects of chronic ethanol feeding. Objective: The goal of this study was to assess the effects of substituting soy isolate for casein to prevent or reduce ethanol’s adverse effects on brain structure and function. Methods: Young adolescent male and female Long Evans were used in a 4-way model as follows: Control + Casein; Ethanol + Casein; Control + Soy; Ethanol + Soy; Control = 0% ethanol; Ethanol = 26% ethanol (caloric). Rats were fed isocaloric diets from 4 to 11 weeks of age. During the final experimental week, the Morris Water maze test was used to assess spatial learning (4 consecutive days), after which the brains were harvested to measure the temporal lobe expression of the total phospho-Akt pathway and downstream target proteins using multiplex bead-based enzyme-linked immunosorbent assays (ELISAs) and duplex ELISAs. Results: Ethanol inhibited spatial learning and reduced brain weight, insulin signaling through Akt, and the expression of ASPH when standard casein was provided as the protein source. The substitution of soy isolate for casein largely abrogated the adverse effects of chronic ethanol feeding. In contrast, Notch signaling protein expression was minimally altered by ethanol or soy isolate. Conclusions: These novel findings suggest that the insulin sensitizer properties of soy isolate may prevent some of the adverse effects that chronic ethanol exposure has on neurobehavioral function and insulin-regulated metabolic pathways in adolescent brains.

BackgroundAdolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month.MethodsUsing the high ethanol‐consuming C57BL/6J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri‐adolescence (postnatal day [P]25 to 70) or adulthood (P180 to 225) of both males and females.ResultsIn control peri‐adolescent animals, body weight gain was greater in males compared with females. In the peri‐adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri‐adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri‐adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro‐caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points.ConclusionsEthanol treatment significantly reduced the mass of the cerebral cortex in peri‐adolescent (−3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (−5.4%), but not peri‐adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri‐adolescent brain.

This study was conducted to determine the temporal and regional vulnerability of the brain as a function of exposure to alcohol during brain development. Our goal was to manipulate the timing of alcohol exposure and assess the relative risk of cell loss in two different brain regions. Groups of timed pregnant Sprague‐Dawley rats received binge‐like alcohol exposure during either the first 10 days (first‐trimester equivalent) or second 10 days of gestation (second‐trimester equivalent), or the combination of first‐ and second‐trimester equivalents for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first‐ and second‐trimester equivalent were reared artificially from postnatal days (P) 4 through 9 (part of the third‐trimester equivalent) and also received binge‐like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also reared artificially and received alcohol from only P4‐9, thus creating animals that were exposed to alcohol only during part of the third‐trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were matched to every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Total cell numbers in the cerebellum (Purkinje and granule cells) and the olfactory bulb (mitral and granule cells) were estimated by the unbiased stereological technique, the optical disector. In terms of temporal vulnerability, alcohol exposure during the equivalent of all three trimesters resulted in a greater reduction in cerebellar Purkinje cell numbers compared with exposure to alcohol during the third‐trimester equivalent, whereas both groups had a significant reduction in cell number compared with all other timing groups. Cerebellar granule cell number was reduced after alcohol exposure during all three trimesters equivalent, compared with all other timing groups. Alcohol exposure during the third‐trimester equivalent resulted in a decrement in the number of olfactory bulb mitral cell numbers compared with all other groups, but there were no differences among the timing groups in numbers of olfactory bulb granule cells. When the cell loss in the two regions was compared within each alcohol treatment group to determine the relative regional vulnerability, the primary salient finding was that cerebellar Purkinje cells were more vulnerable to alcohol‐induced loss subsequent to exposure during all three trimesters equivalent. No other regional differences were detected. These results extend earlier findings by showing that alcohol exposure during different periods of brain development results in regional differences in cell loss as a function of the timing of alcohol exposure during brain development and illustrate the variability of alcohol‐induced neuronal loss.

Sedentary/inactive lifestyle leads middle-aged and older adults to metabolic syndrome and frailty. Capsinoids from nonpungent chili pepper cultivar have been reported to reduce body fat mass, promote metabolism, and improve unidentified complaints of chills. Additionally, they have an anti-inflammation effect; therefore, we hypothesized that continuous oral ingestion of capsinoids alleviates age-related inflammation in the brain and improves the physical activity (PA) in middle-aged and older adults. In our double-blind human study, 69 participants (17 male, 52 female; mean age: 74.1 ± 7.7 years; range: 52–87 years) were administered either 9 mg of capsinoids which were extracted from pepper fruit variety CH-19 Sweet (Capsicum anuum L.) (CP group), or a placebo (PL group) daily over a 3 month period. In an animal study, PA and inflammation-related mRNA expression in the brain were examined in 5-week (young) and 53-week (old) aged mice fed a diet with or without 0.3% dihydrocapsiate, a type of capsinoids, for 12 weeks. In a human study, capsinoids intake did not increase the amount of light-to-moderate PA less than 6.0 metabolic equivalents (METs) (CP: 103.0 ± 28.2 at baseline to 108.2 ± 28.3 at 12 weeks; PL: 104.6 ± 19.8 at baseline to 115.2 ± 23.6 at 12 weeks, METs × hour/week); however, in participants exhibiting an inactive lifestyle, it showed significant increase (CP: 84.5 ± 17.2 at baseline to 99.2 ± 24.9 at 12 weeks; PL: 99.7 ± 23.3 at baseline to 103.8 ± 21.9 at 12 weeks). The energy expenditure in physical activity also improved in the inactive CP group (CP: 481.2 ± 96.3 at baseline to 562.5 ± 145.5 at 12 weeks; PL: 536.8 ± 112.2 at baseline to 598.6 ± 127.6 at 12 weeks; kcal/day). In all participants, CP showed reduced waist circumference, percent body fat, and visceral fat volume; in addition, chills were eased in subjects aged 80 years and older. The older mice fed capsinoids showed increased locomotion activity, decreased inflammation, and oxidative stress in the brain. The results suggest that the continuous oral ingestion of capsinoids gains PA through anti-inflammation effect in the brain as well as reduces fat accumulation and chills in inactive and older humans.