Sustained feeding of a diet high in fat resulted in a decline in the liver's insulin-degrading enzyme levels in association with the induction of oxidative and endoplasmic reticulum stress in adult male rats: Evaluation of 4-phenylbutyric acid.

The current study explored the impact of high fat diet (HFD) on hepatic oxidative and endoplasmic reticulum (ER) stress and its insulin degrading enzyme (IDE) content with the injection of 4-phenyl butyric acid (4-PBA) in adult male rats. Following the weaning period, male offspring were distributed among six distinct groups. The corresponding diet was used for 20 weeks, subsequently 4-PBA was administered for three consecutive days. Plasma glucose and insulin levels, HOMA-ß (homeostasis model assessment of ß-cell), hepatic ER and oxidative stress biomarkers and IDE protein content were assessed. Long-term ingestion of HFD (31 % cow butter) induced oxidative and ER stress in the liver tissue. Accordingly, a rise in the malondialdehyde (MDA) content and catalase enzyme activity and a decrease in the glutathione (GSH) content were detected within the liver of the HFD and HFD + DMSO groups. Consumption of this diet elevated the liver expression of binding immunoglobulin protein (BIP) and C/enhancer-binding protein homologous protein (CHOP) levels while reduced its IDE content. The HOMA-ß decreased significantly. The injection of the 4-PBA moderated all the induced changes. Findings from this study indicated that prolonged HFD consumption led to a reduction in plasma insulin levels, likely attributed to pancreatic ß cell malfunction, as evidenced by a decline in the HOMA-ß index. Also, the HFD appears to have triggered oxidative and ER stress in the liver, along with a decrease in its IDE content.

Effects of sub-chronic CRH administration into the hypothalamic paraventricular and central amygdala nuclei in male rats with a focus on food intake biomarkers.

CRH neurons are found in the paraventricular nucleus(PVN) and central amygdala(CeA) nuclei. This study investigated the effects of sub-chronic CRH administration into the PVN and CeA nuclei on food intake biomarkers in rats divided into five groups: control, two shams, and two CRH-PVN and CRH-CeA groups(receiving CRH in nuclei for seven days). The CRH-PVN group had significantly higher cumulative food intake and food intake trends than the CRH-CeA group. The CRH-CeA and CRH-PVN groups exhibited significant increases in food intake during hours 1 and 2, respectively. Moreover, to be time-dependent, food intake is modulated by different brain nuclei. The CRH signaling pathway appeared to be activated later in the PVN than CeA. Both groups exhibited significantly higher leptin levels, the CRH-PVN group exhibited higher ghrelin levels and lower glucose levels. Repetitive administration of CRH into the PVN and CeA significantly reduced body weight differences. CRH administration into the PVN affected both leptin and ghrelin levels, but ghrelin had a greater impact on glucose variations and cumulative food intake than leptin. Finally, CRH administration into the PVN and CeA likely activated the HPA axis, and the CeA had a greater impact on the stress circuit than on food intake behavior.

Oxidative and endoplasmic reticulum stress develop adverse metabolic effects due to the high-fat high-fructose diet consumption from birth to young adulthood.

AIMS: The early postnatal dietary intake has been considered a crucial factor affecting the offspring later life metabolic status. Consistently, this study investigated the oxidative and endoplasmic reticulum (ER) stress interventions in the induction of adverse metabolic effects due to the high-fat high-fructose diet (HFHFD) consumption from birth to young adulthood in rat offspring. MATERIALS AND METHODS: After delivery, the dams with their pups were randomly allocated into the normal diet (ND) and HFHFD groups. At weaning, the male offspring were divided into ND-None, ND-DMSO, ND-4-phenyl butyric acid (4-PBA), HFHFD-None, HFHFD-DMSO, and HFHFD-4-PBA groups and fed on their respected diets for five weeks. Then, the drug was injected for ten days. Subsequently, glucose and lipid metabolism parameters, oxidative and ER stress markers, and Wolfram syndrome1 (Wfs1) expression were assessed. KEY FINDINGS: In the HFHFD group, anthropometrical parameters, plasma high-density lipoprotein (HDL), and glucose-stimulated insulin secretion and content were decreased. Whereas, the levels of plasma leptin, low-density lipoprotein (LDL) and glucose, hypothalamic leptin, pancreatic catalase activity and glutathione (GSH), pancreatic and hypothalamic malondialdehyde (MDA), binding immunoglobulin protein (BIP) and C/EBP homologous protein (CHOP), and pancreatic WFS1 protein were increased. 4-PBA administration in the HFHFD group, decreased the hypothalamic and pancreatic MDA, BIP and CHOP levels, while, increased the Insulin mRNA and glucose-stimulated insulin secretion and content. SIGNIFICANCE: HFHFD intake from birth to young adulthood through the development of pancreatic and hypothalamic oxidative and ER stress, increased the pancreatic WFS1 protein and impaired glucose and lipid homeostasis in male rat offspring.

Overview of the central amygdala role in feeding behaviour.

The neural regulation of feeding behaviour, as an essential factor for survival, is an important research area today. Feeding behaviour and other lifestyle habits play a major role in optimising health and obesity control. Feeding behaviour is physiologically controlled through processes associated with energy and nutrient needs. Different brain nuclei are involved in the neural regulation of feeding behaviours. Therefore, understanding the function of these brain nuclei helps develop feeding control methods. Among important brain nuclei, there is scant literature on the central amygdala (CeA) nucleus and feeding behaviour. The CeA is one of the critical brain regions that play a significant role in various physiological and behavioural responses, such as emotional states, reward processing, energy balance and feeding behaviour. It contains γ-aminobutyric acid neurons. Also, it is the major output region of the amygdaloidal complex. Moreover, the CeA is also involved in multiple molecular and biochemical factors and has extensive connections with other brain nuclei and their neurotransmitters, highlighting its role in feeding behaviour. This review aims to highlight the significance of the CeA nucleus on food consumption by its interaction with the performance of reward, digestive and emotional systems.

ComparativeStudyofCRHMicroinjections Into PVN and CeA Nuclei on Food Intake, Ghrelin, Leptin, and Glucose Levels in Acute Stressed Rats.

INTRODUCTION: Corticotropin-Releasing Hormone (CRH) is involved in stress and energy homeostasis. On the other hand, CRH receptors also exist within the paraventricular nucleus (PVN) and Central Amygdala (CeA) nuclei. The present study compared the effect of CRH microinjections into PVN and CeA on three consecutive hours and cumulative food intake, internal regulatory factors of food intake, such as serum leptin and ghrelin, as well as blood glucose levels in rats under different acute psychological (Social Stress [SS] and Isolation Stress [IS] group) stresses. METHODS: Sixty-six male Wistar rats were randomly allocated to 11 groups: Control, Sham, CRH-PVN, CRH-CeA, SS, IS, SS-CRH-PVN, SS-CRH-CeA, IS-CRH-PVN, and IS-CRH-CeA groups. The CRH (2 µg/kg in 0.5 µL saline) was injected into PVN and CeA nuclei in rats under everyday, acute social stress and isolation stress conditions. RESULTS: Acute isolation and social stresses did not affect cumulative food intake. Whereas isolation stress led to changes in both leptin and glucose levels, social stress reduced only glucose levels. Cumulative food intake significantly decreased under acute CRH injection into the CeA and particularly into the PVN. Blood glucose significantly reduced in all the groups receiving CRH into their CeA. CONCLUSION: The PVN played a more important role compared to CeA on food intake. These nuclei probably employ different mechanisms for their effects on food intake. Besides, it seems that exogenously CRH injection into the PVN probably had a more anorectic effect than naturally activated CRH by stresses. Acute isolation stress had a greater impact than social stress on leptin level and cumulative food intake. Thus, elevated food intake related to leptin compared to ghrelin and glucose levels in the CRH-PVN group under acute social stress.

Effects of Isolation and Social Subchronic Stresses on Food Intake and Levels of Leptin, Ghrelin, and Glucose in Male Rats.

BACKGROUND: Exposure to psychological stresses can be a reason for obesity. Therefore, identifying the effective nutritional mechanisms such as feeding markers is of high necessity for the psychological stress conditions. Hence, the present study investigates the effects of subchronic isolation and social stresses on food intake, body weight differences (BWD), and levels of leptin, ghrelin, and glucose in rats. MATERIALS AND METHODS: Eighteen male rats were randomly allocated into three groups: control (Co), isolation stress (IS), and social stress (SS) groups. Rats were under stresses for 7 days. The food intake (for three continuous hours after 16-18 h of food deprivation), BWD, levels of ghrelin, leptin, and glucose were measured. RESULTS: The results showed that the food intake significantly (P < 0.05) reduced during the 1st h in the SS group compared to the Co group. At the 2nd h, the food intake significantly (P < 0.001 and P < 0.01, respectively) decreased in the IS group compared to the Co and SS groups. The cumulative food intake and body weight were significantly (P < 0.05) reduced in the IS group compared to the Co group. The serum ghrelin level significantly reduced in the IS group compared to the Co group. CONCLUSIONS: The subchronic psychological stresses led to a reduction in food intake by the reduction of serum ghrelin levels. It seems that ghrelin might have a more fundamental role in the food intake with respect to the leptin and glucose levels in subchronic stress condition. Furthermore, the decreased body weight justified the reduction of food intake, particularly in subchronic isolation stress.

Two-view digital breast tomosynthesis screening with synthetically reconstructed projection images: comparison with digital breast tomosynthesis with full-field digital mammographic images.

PURPOSE: To compare the performance of two versions of reconstructed two-dimensional (2D) images in combination with digital breast tomosynthesis (DBT) versus the performance of standard full-field digital mammography (FFDM) plus DBT. MATERIALS AND METHODS: This trial had ethical committee approval, and all participants gave written informed consent. Examinations (n = 24 901) in women between the ages of 50 and 69 years (mean age, 59.2 years) were interpreted prospectively as part of a screening trial that included independent interpretations of FFDM plus DBT and reconstructed 2D images plus DBT. Reconstructed 2D images do not require radiation exposure. Using analyses for binary data that accounted for correlated interpretations and were adjusted for reader-specific volume, two versions (initial and current) of reconstructed 2D images used during trial periods 1 (from November 22, 2010, to December 21, 2011; 12 631 women) and 2 (from January 20, 2012, to December 19, 2012; 12 270 women) were compared in terms of cancer detection and false-positive rates with the corresponding FFDM plus DBT interpretations. RESULTS: Cancer detection rates were 8.0, 7.4, 7.8, and 7.7 per 1000 screening examinations for FFDM plus DBT in period 1, initial reconstructed 2D images plus DBT in period 1, FFDM plus DBT in period 2, and current reconstructed 2D images plus DBT in period 2, respectively. False-positive scores were 5.3%, 4.6%, 4.6%, and 4.5%, respectively. Corresponding reader-adjusted paired comparisons of false-positive scores revealed significant differences for period 1 (P = .012) but not for period 2 (ratio = 0.99; 95% confidence interval: 0.88, 1.11; P = .85). CONCLUSION: The combination of current reconstructed 2D images and DBT performed comparably to FFDM plus DBT and is adequate for routine clinical use when interpreting screening mammograms.

Prospective trial comparing full-field digital mammography (FFDM) versus combined FFDM and tomosynthesis in a population-based screening programme using independent double reading with arbitration.

OBJECTIVES: To compare double readings when interpreting full field digital mammography (2D) and tomosynthesis (3D) during mammographic screening. METHODS: A prospective, Ethical Committee approved screening study is underway. During the first year 12,621 consenting women underwent both 2D and 3D imaging. Each examination was independently interpreted by four radiologists under four reading modes: Arm A-2D; Arm B-2D + CAD; Arm C-2D + 3D; Arm D-synthesised 2D + 3D. Examinations with a positive score by at least one reader were discussed at an arbitration meeting before a final management decision. Paired double reading of 2D (Arm A + B) and 2D + 3D (Arm C + D) were analysed. Performance measures were compared using generalised linear mixed models, accounting for inter-reader performance heterogeneity (P < 0.05). RESULTS: Pre-arbitration false-positive scores were 10.3 % (1,286/12,501) and 8.5 % (1,057/12,501) for 2D and 2D + 3D, respectively (P < 0.001). Recall rates were 2.9 % (365/12,621) and 3.7 % (463/12,621), respectively (P = 0.005). Cancer detection was 7.1 (90/12,621) and 9.4 (119/12,621) per 1,000 examinations, respectively (30 % increase, P < 0.001); positive predictive values (detected cancer patients per 100 recalls) were 24.7 % and 25.5 %, respectively (P = 0.97). Using 2D + 3D, double-reading radiologists detected 27 additional invasive cancers (P < 0.001). CONCLUSION: Double reading of 2D + 3D significantly improves the cancer detection rate in mammography screening. KEY POINTS: • Tomosynthesis-based screening was successfully implemented in a large prospective screening trial. • Double reading of tomosynthesis-based examinations significantly reduced false-positive interpretations. • Double reading of tomosynthesis significantly increased the detection of invasive cancers.

Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program.

PURPOSE: To assess cancer detection rates, false-positive rates before arbitration, positive predictive values for women recalled after arbitration, and the type of cancers detected with use of digital mammography alone and combined with tomosynthesis in a large prospective screening trial. MATERIALS AND METHODS: A prospective, reader- and modality-balanced screening study of participants undergoing combined mammography plus tomosynthesis, the results of which were read independently by four different radiologists, is under way. The study was approved by a regional ethics committee, and all participants provided written informed consent. The authors performed a preplanned interim analysis of results from 12,631 examinations interpreted by using mammography alone and mammography plus tomosynthesis from November 22, 2010, to December 31, 2011. Analyses were based on marginal log-linear models for binary data, accounting for correlated interpretations and adjusting for reader-specific performance levels by using a two-sided significance level of .0294. RESULTS: Detection rates, including those for invasive and in situ cancers, were 6.1 per 1000 examinations for mammography alone and 8.0 per 1000 examinations for mammography plus tomosynthesis (27% increase, adjusted for reader; P = .001). False-positive rates before arbitration were 61.1 per 1000 examinations with mammography alone and 53.1 per 1000 examinations with mammography plus tomosynthesis (15% decrease, adjusted for reader; P < .001). After arbitration, positive predictive values for recalled patients with cancers verified later were comparable (29.1% and 28.5%, respectively, with mammography alone and mammography plus tomosynthesis; P = .72). Twenty-five additional invasive cancers were detected with mammography plus tomosynthesis (40% increase, adjusted for reader; P < .001). The mean interpretation time was 45 seconds for mammography alone and 91 seconds for mammography plus tomosynthesis (P < .001). CONCLUSION: The use of mammography plus tomosynthesis in a screening environment resulted in a significantly higher cancer detection rate and enabled the detection of more invasive cancers. Clinical trial registration no. NCT01248546.