Pancreatic GLUT2 protein expression and isolated islets insulin secretion decreased in high-fat fed rat dams.

Purpose: Chronic consumption of high-fat foods during the reproductive period may endanger the dams' metabolic homeostasis and might adversely affect pregnancy outcome. In this regard the present study aimed to investigate the effect of long-term high-fat feeding on pancreatic glucose transporter-2 (GLUT2) protein expression and isolated islets glucose-stimulated insulin secretion in Wistar rat dams. Materials and methods: Female rats were randomly divided into normal (N) and high-fat (HF; containing cow butter) diet groups and consumed their respective diets for 10 weeks (from prepregnancy to the end of lactation). After lactation, fasting plasma concentrations of glucose and insulin were measured to calculate HOMA-IR index, then intraperitoneal glucose tolerance test (IPGTT) was performed. Moreover, the pancreatic GLUT2 protein expression and insulin secretion from isolated islets at basal (5.6 mM) and stimulated (16.7 mM) glucose concentrations were assessed. Results: In HF group compared to N group, the plasma insulin level increased, whereas the plasma glucose level did not change in fasting state. Accordingly, the HOMA-IR index increased in HF fed animals. Furthermore, the IPGTT revealed glucose intolerance based on the plasma glucose and insulin results. Also, the pancreatic GLUT2 expression and isolated islets insulin secretion, in response to high glucose concentration, were decreased. Conclusion: The chronic consumption of high-fat foods during prepregnancy, pregnancy, and lactation periods can lead to glucose intolerance, insulin resistance, and inhibition of pancreatic GLUT2 expression, which impairs glucose homeostasis. Therefore, it is crucial to carefully monitor the diet composition of dams during this critical period. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01274-6.

Endoplasmic reticulum stress inhibition ameliorated WFS1 expression alterations and reduced pancreatic islets' insulin secretion induced by high-fat diet in rats.

Endoplasmic reticulum (ER) stress is involved in the development of glucose homeostasis impairment. When ER stress occurs, the unfolded protein response (UPR) is activated to cope with it. One of the UPR components is WFS1 (Wolfram syndrome 1), which plays important roles in ER homeostasis and pancreatic islets glucose-stimulated insulin secretion (GSIS). Accordingly and considering that feeding high-fat food has a major contribution in metabolic disorders, this study aimed to investigate the possible involvement of pancreatic ER stress in glucose metabolism impairment induced by feeding high-fat diet (HFD) in male rats. After weaning, the rats were divided into six groups, and fed on normal diet and HFD for 20 weeks, then 4-phenyl butyric acid (4-PBA, an ER stress inhibitor) was administered. Subsequently, in all groups, after performing glucose tolerance test, the animals were dissected and their pancreases were removed to extract ER, islets isolation and assessment of GSIS. Moreover, the pancreatic ER stress [binding of immunoglobulin protein (BIP) and enhancer-binding protein homologous protein (CHOP)] and oxidative stress [malondialdehyde (MDA), glutathione (GSH) and catalase] biomarkers as well as WFS1 expression level were evaluated. HFD decreased pancreatic WFS1 protein and GSH levels, and enhanced pancreatic catalase activity, MDA content, BIP and CHOP protein and mRNA levels as well as Wfs1 mRNA amount. Accordingly, it increased BIP, CHOP and WFS1 protein levels in the extracted ER of pancreas. In addition, the HFD caused glucose intolerance, and decreased the islets' GSIS and insulin content. However, 4-PBA administration restored the alterations. It seems that, HFD consumption through inducing pancreatic ER stress, altered WFS1 expression levels, reduced the islets' GSIS and insulin content and finally impaired glucose homeostasis.

Investigating the Effects of Maternal Separation on Hypothalamic-Pituitary-Adrenal Axis and Glucose Homeostasis under Chronic Social Defeat Stress in Young Adult Male Rat Offspring.

INTRODUCTION: Given the suggested metabolic regulatory effects of stress-responsive genes and based on the impacts of early-life stress on HPA axis development, this study aimed to characterize the maternal separation (MS) impact on the communication between glucose metabolism and HPA axis dysregulations under chronic social defeat stress (CSDS). METHODS: During the first 2 weeks of life, male Wistar rats were either exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. There were four groups (n = 10/group): Std-Con, MS-Con, Std-CSDS, and MS-CSDS. RESULTS: Early and/or adult life adversity reduced ß-cell number, muscular FK506-binding protein 51 (FKBP51) content, and BMI in adulthood. The reduction of ß-cell number and BMI in the MS-CSDS rats were more profound than MS-Con group. CSDS either alone or in combination with MS reduced locomotor activity and increased and decreased corticotropin-releasing factor type 1 receptor (CRFR1) content, respectively, in hypothalamus and pancreas. Although, under CSDS, MS intensified HPA axis overactivity and reduced isolated islets' insulin secretion, it could promote resilience to depression symptoms. No differences were observed in hypothalamic Fkbp5 gene DNA methylation and glucose tolerance among groups. CONCLUSION: MS exacerbated HPA axis overactivity and the endocrine pancreas dysfunctions under CSDS. The intensified corticosterone secretion and the diminished content of pancreatic CRFR1 protein could be involved in the reduced ß-cell number and islets' insulin secretion under CSDS. The decreased muscular FKBP51 content might be a homeostatic response to slow down insulin resistance development under chronic stress.

Long-term high-fat diet disrupts lipid metabolism and causes inflammation in adult male rats: possible intervention of endoplasmic reticulum stress.

This study investigated the effect of long-term high-fat diet (HFD) on plasma lipid profile and probability of inflammation in adult rats. After weaning, male offspring were divided into six groups based on diet type and medication. After 20 weeks of dietary intake, 4-PBA (endoplasmic reticulum (ER) stress inhibitor) was injected for three days. Then, blood samples were taken to measure plasma concentrations of low-density lipoprotein (LDL), triglyceride (TG), high-density lipoprotein (HDL), cholesterol, leptin and interleukin 1-ß (IL 1-ß). The HFD increased body weight and food intake and intra-abdominal fat and thymus weights, which were associated with elevated plasma leptin level. Moreover, HFD increased plasma concentrations of TG, LDL, cholesterol and IL 1-ß and decreased HDL level. Injection of 4-PBA reversed the plasma parameters changes caused by HFD. It seems that long-term HFD feeding through inducing the ER stress, disrupted the lipid metabolism and resulted in inflammation.

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.

Maternal stress induced endoplasmic reticulum stress and impaired pancreatic islets' insulin secretion via glucocorticoid receptor upregulation in adult male rat offspring.

Exposure to perinatal (prenatal and/or postnatal) stress is considered as a risk factor for metabolic disorders in later life. Accordingly, this study aimed to investigate the perinatal stress effects on the pancreatic endoplasmic reticulum (ER) stress induction, insulin secretion impairment and WFS1 (wolframin ER transmembrane Glycoprotein, which is involved in ER homeostasis and insulin secretion) expression changes, in rat offspring. According to the dams' period of exposure to variable stress, their male offspring were divided into, control (CTRL); pre-pregnancy, pregnancy, lactation stress (PPPLS); pre-pregnancy stress (PPS); pregnancy stress (PS); lactation stress (LS); pre-pregnancy, pregnancy stress (PPPS); pregnancy, lactation stress (PLS); pre-pregnancy, lactation stress (PPLS) groups. Offspring pancreases were removed for ER extraction and the assessment of ER stress biomarkers, WFS1 gene DNA methylation, and isolated islets' insulin secretion. Glucose tolerance was also tested. In the stressed groups, maternal stress significantly increased plasma corticosterone levels. In PPS, PS, and PPPS groups, maternal stress increased Bip (Hsp70; heat shock protein family A member 4), Chop (Ddit3; DNA- damage inducible transcript3), and WFS1 protein levels in pancreatic extracted ER. Moreover, the islets' insulin secretion and content along with glucose tolerance were impaired in these groups. In PPS, PS, LS and PPPS groups, the pancreatic glucocorticoid receptor (GR) expression increased. Maternal stress did not affect pancreatic WFS1 DNA methylation. Thus, maternal stress, during prenatal period, impaired the islets' insulin secretion and glucose homeostasis in adult male offspring, possibly through the induction of ER stress and GR expression in the pancreas, in this regard the role of WFS1 protein alteration in pancreatic ER should also be considered.

Perinatal stress exposure induced oxidative stress, metabolism disorder, and reduced GLUT-2 in adult offspring of rats.

PURPOSE: Growing evidence has demonstrated that adversity in early life, especially in the prenatal and postnatal period, may change the programming of numerous body systems and cause the incidence of various disorders in later life. Accordingly, this experimental animal study aimed to investigate the effect of stress exposure during perinatal (prenatal and/or postnatal) on the induction of oxidative stress in the pancreas and its effect on glucose metabolism in adult rat offspring. METHODS: In this experimental study based on maternal exposure to variable stress throughout the perinatal period, the pups were divided into eight groups, as follows: control group (C); prepregnancy, pregnancy, lactation stress group (PPPLS); prepregnancy stress group (PPS); pregnancy stress group (PS); lactation stress group (LS); prepregnancy, pregnancy stress group (PPPS); pregnancy, lactation stress group (PLS); and prepregnancy, lactation stress group (PPLS). Following an overnight fast on postnatal day (PND) 64, plasma glucose, insulin, leptin levels, and lipid profiles were evaluated in the offspring groups. GLUT-2 protein levels, lipid peroxidation, antioxidant status, and number of beta-cells in the pancreatic islets of Langerhans as well as the weights of intra-abdominal fat and adrenal glands were assessed. Levels of plasma corticosterone were determined in the different groups of mothers and offspring. RESULTS: The levels of plasma corticosterone, insulin, and HOMA-B index increased, whereas glucose level and QUICKI index were reduced in the perinatal stress groups compared to C group (p < 0.001 to p < 0.05). Plasma triglyceride, LDL, and cholesterol level rose significantly, but HDL level decreased in the perinatal stress groups compared to C group (p < 0.001 to p < 0.05). Perinatal stress raised MDA concentrations and reduced the activities of antioxidant enzymes in plasma and pancreas compared to C group (p < 0.001 to p < 0.05). GLUT-2 protein levels and number of beta-cells in the stress groups declined compared to C group (p < 0.001 to p < 0.05). Intra-abdominal fat weight decreased in the PPS, PS, and LS groups compared to C group (p < 0.001 to p < 0.01), but adrenal gland weight remained unchanged. CONCLUSION: Our results showed that long-term exposure to elevated levels of corticosterone during critical development induces metabolic syndrome in adult male rats.

Maternal separation induced resilience to depression and spatial memory deficit despite intensifying hippocampal inflammatory responses to chronic social defeat stress in young adult male rats.

Early life adversity has been suggested to affect neuroendocrine responses to subsequent stressors and accordingly vulnerability for behavioral disorders. This is the first work to study the effects of maternal separation (MS) stress on the co-occurrence of depression and cognitive impairments along with hippocampal inflammatory response under chronic social defeat stress (CSDS) in young adult male rats. During the first two postnatal weeks, the male pups were either exposed to MS or left undisturbed with their mothers (Std). Subsequently, starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for three weeks. Totally, there were four groups (n = 10/group), namely Std-Con, Ms-Con, Std-CSDS, and MS-CSDS. Pup retrieval test was performed on daily basis from PND1 to PND14. During the last week of the CSDS exposure, in the light phase, the behavioral tests and the retro-orbital blood sampling were performed to assess basal plasma corticosterone levels. Afterwards, the hippocampus of the animals was removed to measure the interleukin 1ß (IL-1ß) content. Exposure to CSDS increased the plasma corticosterone levels and induced social avoidance along with memory deficit. Maternal separation intensified hippocampal IL-1ß contents as well as the plasma corticosterone levels in response to CSDS. Meanwhile, it facilitated the spatial learning and potentiated resilience to social avoidance and memory deficit. In conclusion, although maternal separation increased the basal plasma corticosterone levels, it could facilitate the learning process and induce resilience to the onset of depression and memory deficit in response to CSDS, probably through the compensatory increase in maternal care and the induction of mild hippocampal inflammatory response.

Investigation of the effects of maternal separation on the pancreatic oxidative and inflammatory damages along with metabolic impairment in response to chronic social defeat stress in young adult male rats.

PURPOSE: Chronic glucocorticoid release during the stress response has been proposed to initiate certain damages, which in turn produce metabolic disorders. The present study is the first work to test whether maternal separation (MS) would impact the metabolic alterations associated with pancreatic oxidative and inflammatory damages under chronic exposure to social defeat stress (CSDS) in adulthood. METHODS: During the first 2 weeks of life, male Wistar rats were exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. Thus, there were 4 groups (n = 7/group): Std-Con, Ms-Con, Std-CSDS, MS-CSDS. Each animal was weighed and then decapitated so that we could collect trunk blood for assessment of fasting plasma corticosterone, insulin, glucose, lipid profile, and insulin resistance. Plasma and pancreatic catalase activity, reduced glutathione (GSH), malondialdehyde levels and pancreatic interleukin-1 beta (IL-1ß) content were also measured. RESULTS: MS-CSDS animals showed elevated plasma corticosterone and insulin levels (P < 0.01) along with insulin resistance (P < 0.05). According to one-way ANOVA results, chronic exposure to early or adult life adversity decreased body weight (P < 0.0001), Catalase activity and GSH levels (P < 0.0001) and increased malondialdehyde level (P = 0.0006) in plasma. Pancreatic MDA and IL-1ß contents elevated just in MS-CSDS rats (P < 0.05). CONCLUSION: Maternal separation shapes vulnerability to develop corticosterone hypersecretion, insulin resistance, pancreatic oxidative, and inflammatory damages associated with chronic exposure to later social challenges, which could potentially trigger metabolic disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00902-3.

The chemical chaperon 4-phenyl butyric acid restored high-fat diet- induced hippocampal insulin content and insulin receptor level reduction along with spatial learning and memory deficits in male rats.

This study assessed the effect of a chronic high-fat diet (HFD) on plasma and hippocampal insulin and corticosterone levels, the hippocampus insulin receptor amount, and spatial learning and memory with or without receiving 4-phenyl butyric acid (4-PBA) in male rats. Rats were divided into high-fat and normal diet groups, then each group was subdivided into dimethyl sulfoxide (DMSO) and 4-PBA groups. After weaning, the rats were fed with HFD for 20 weeks. Then, 4-PBA or DMSO were injected for 3 days. Subsequently, oral glucose tolerance test was done. On the following day, spatial memory tests were performed. Then the hippocampus Bip, Chop, insulin, corticosterone, and insulin receptor levels were determined. HFD increased plasma glucose, leptin and corticosterone concentrations, hippocampus Bip, Chop and corticosterone levels, food intake, abdominal fat weight and body weight along with impaired glucose tolerance. It decreased plasma insulin, and insulin content, and its receptor amount in hippocampus. HFD lengthened escape latency and shortened the duration spent in target zone. 4-PBA administration improved the HFD- induced adverse changes. Chronic HFD possibly through the induction of endoplasmic reticulum (ER) stress and subsequent changes in the levels of hippocampal corticosterone, insulin and insulin receptor along with possible leptin resistance caused spatial learning and memory deficits.

Pancreatic HB9 protein level is affected by early life stress in young adult rats: possible involvement of TNF-α and corticosterone.

This study examined foot shock stress effects, during weaning, on pancreatic HB9 protein expression in young adult male rats in the presence or absence of adulthood stress. The pups were divided into Control, Early life stress, Young adult stress, and Early + young adult stress groups. Plasma corticosterone, insulin, glucose, and TNF-α concentrations, and pancreatic HB9 protein expression were assessed. At 2 weeks of age, stress increased plasma corticosterone level. During young adulthood, plasma TNF-α and glucose concentrations increased, whereas plasma insulin and pancreatic HB9 protein levels decreased in Early life stress group. Whereas, Early + young adulthood stress group showed no change in the study parameters, except for plasma corticosterone and insulin concentrations. Overall, early life stress reduced pancreatic HB9 protein expression possibly by elevating plasma corticosterone and TNF-α levels in early life and adulthood, respectively. However, combined with adulthood stress, HB9 protein expression increased to the level of Control.

Early-life stress altered pancreatic Krebs cycle-related enzyme activities in response to young adulthood physical and psychological stress in male rat offspring.

OBJECTIVES: Early-life stress (ELS) increases the risk of metabolic disorders in later life. The present study investigated the ELS effect on pancreatic pyruvate dehydrogenase (PDH) protein level, α-ketoglutarate dehydrogenase (α-KGDH), and aconitase activities as metabolic enzymes in response to young adulthood stress in male rat offspring. METHODS: Male Wistar rats were divided into six groups: Control, early life stress (Early STR), young adult foot-shock stress (Y. adult F-SH STR), early + young adult foot-shock stress (Early + Y. adult F-SH STR), young adult psychological stress (Y. adult Psy STR) and early + young adult psychological stress (Early + Y. adult Psy STR). Stress was induced by a communication box at 2 weeks of age and young adulthood for five consecutive days. The blood samples were collected in young adult rats, then pancreases were removed to measure its PDH protein level and aconitase and α-KGDH activities. RESULTS: In ELS animals, applying foot-shock stress in young adulthood increased PDH protein level, decreased α-KGDH and aconitase activities, and increased plasma glucose, insulin, and corticosterone concentrations. However, exposure to young adulthood psychological stress only decreased α-KGDH and aconitase activities. CONCLUSIONS: It seems that ELS altered metabolic response to young adulthood stress through changes of Krebs cycle-related enzymes activities, though the type of adulthood stress was determinant.

Early postnatal hypothalamic-pituitary-adrenal axis activity and reduced insulin sensitivity in adult rats.

OBJECTIVE: Early life stress influences the development of metabolic disorders, including functional changes in the developing of pancreas mediated hypothalamic-pituitary-adrenal (HPA) axis. In the present study, the role of an early postnatal stress on corticosterone, glucose, and insulin levels was investigated during young adulthood. METHODS: Two groups of pups were studied, including control group (pups not receiving foot shock by communication box), and early stress group (pups receiving foot shock by communication box 2 times/day for 5 consecutive days). In rats, concentration of plasma corticosterone, glucose, and insulin was detected before and after placing them into the communication box at 2 weeks of age. At 8-10 weeks of age, concentrations of plasma corticosterone, glucose, and insulin and glucose tolerance were measured in young adult rats. RESULTS: Our results showed that early postnatal foot shock stress increased the corticosterone, insulin, and glucose levels in the postnatal age (p<0.01) that did not last until young adult age, but it caused a significant increase in plasma glucose and insulin levels (p<0.05) following the intraperitoneal glucose tolerance test (IPGTT) in young adult rats. CONCLUSIONS: These results suggest that impaired IPGTT in young adult rats who experienced early postnatal stress can indicate insulin resistance or reduced insulin sensitivity that make it at risk of the type 2 diabetes later in life.

DIBc, a nanochelating-based nano metal-organic framework, shows anti-diabetic effects in high-fat diet and streptozotocin-induced diabetic rats.

AIMS: Despite daily increase in diabetic patients in the world, currently approved medications for this disease, at best, only reduce its progression speed. Using novel technologies is a solution for synthetizing more efficient medicines. In the present study, we evaluated anti-diabetic effects of DIBc, a nano metal-organic framework, which is synthetized based on nanochelating technology. METHODS: High-fat diet and streptozotocin-induced diabetic rats were treated by DIBc or metformin for 6 weeks. RESULTS: DIBc decreased plasma glucose, triglyceride, cholesterol, high-density lipoprotein, and low-density lipoprotein compared with diabetic and metformin groups. In DIBc-treated rats, significant homeostasis model assessment of insulin resistance index, malondialdehyde, and tumor necrosis factor-α decrease was observed. H&E staining showed increased islet number and area in DIBc-treated rats compared with diabetic controls. CONCLUSION: The results showed anti-diabetic effects of nanochelating-based framework. So DIBc, as a nano structure, has the capacity to be evaluated in future studies as a novel anti-diabetic agent.

Correction: Maternal separation blunted spatial memory formation independent of peripheral and hippocampal insulin content in young adult male rats.

[This corrects the article DOI: 10.1371/journal.pone.0204731.].

Time-course study of high fat diet induced alterations in spatial memory, hippocampal JNK, P38, ERK and Akt activity.

Consumption of high fat diet (HFD) is a health concern in modern societies, which participate in wide range of diseases. One underlying mechanism in the HFD mediated pathologies is disruption of insulin signaling activity. It is believed that HFD activates several stress signaling molecules such as MAPKs signaling pathway and these molecules participate in harmful effects in different cell populations including hippocampal cells. However, the activity of MAPKs signaling molecules are time dependent, even causing some opposing effects. Given that, MAPKs activity fluctuate with time of stress, there is less cleared how different lengths of HFD consumption can affect hippocampal MAPK. To test how duration of HFD consumption affect hippocampal MAPKs and insulin signaling activity and animal's cognitive function, rats were fed with HFD for different lengths (up to 6 months) and after each point spatial memory performances of animals was tested, then the peripheral indices of insulin resistance and hippocampal MAPKs and insulin signaling activity was evaluated. Results showed that while different time courses of HFD, up to 6 months, did not bring about significant spatial memory impairment, meanwhile the peripheral insulin sensitivity as well as hippocampal insulin and MAPKs signaling showed significant fluctuations during the different time courses of high fat diet regime. These results showed that neuronal responses to HFD is not constant and differ in a time-dependent manner, it seems that in acute phase molecular responses aimed to compensate the HFD stress but in chronic states these responses failed and devastating effects of stress began.

Maternal separation blunted spatial memory formation independent of peripheral and hippocampal insulin content in young adult male rats.

This study explores the effects of maternal separation as a chronic early life stress (ELS) on pancreatic islets insulin content and secretion, and their potential relationship with the hippocampus insulin content and spatial memory in young adulthood. Male rat offspring were divided into two groups: stress (STR) and non-stress (non-STR) groups. The animals of the STR group were separated from their mothers during postnatal days (PND) 1 to 21. During the weaning time, that is, PND-0 to PND-21, the body weight and length of the pups were measured. Blood samples were collected on PND-1, 21, 29 and 34 and during young adulthood (53±2 days) to determine plasma corticosterone and insulin levels. The young adult animals were also tested for spatial memory. One day after the memory test, the animals were decapitated and their pancreases were removed to measure the islets insulin content and secretion. Finally, the animals' hippocampi were isolated to determine their insulin content and insulin receptor protein amounts. During the period of weaning, the body weight and length of pups belonging to the STR group were significantly lower as compared to those in the non-STR group. Maternal separation did not change the plasma levels of insulin but increased plasma corticosterone levels from PND-21 to young adulthood and also reduced the islets insulin content but did not affect insulin secretion and the hippocampus insulin content and insulin receptor protein amount. Although, at the end of the memory tests, rats of the STR group reached the escape box at almost the same time and distance and with the same errors as rats of the non-STR group, the distance traveled to reach the escape box showed a steep reduction in the non-STR group as compared to the STR group after the first trial. Moreover, as compared to the STR group, the non-STR group showed an increasing trend for direct strategy to find the escape box. The islets insulin content and secretion, and the plasma insulin concentration were not significantly correlated with the hippocampus insulin content. From the results of the present study, it appears that the main behavioral effect of the maternal separation stress in the spatial memory task was to impair the strategy used by the animals to reach the escape box. This may indicate that maternal separation stress affects brain regions other than the hippocampus. Moreover, due to the reduction of the body weight and length of offspring belonging to the STR group, it should be further considered that both maternal separation and early life malnutrition are directly (and mechanistically) linked to cognitive alterations later in life in ways that are not dependent on peripheral and hippocampal insulin content.

High-fat diet effects on metabolic responses to chronic stress.

CONTEXT: High-fat diets and chronic stress are prevalent risk factors for various chronic diseases in modern societies. OBJECTIVE: This study investigated the effect of high-fat diet on glucose-related metabolic responses to chronic foot-shock stress. MATERIALS AND METHODS: Male rats were divided into high-fat diet (containing 54.21% saturated and 44.89% unsaturated fatty acids) and normal diet groups and then into stress and non-stress subgroups. The diets were applied for 5 weeks, and stress was induced during the last week of the diet course. Plasma levels of metabolic parameters, HOMA-IR index, intra-abdominal fat weight, and islets' insulin secretion were assessed. RESULTS: High-fat diet increased abdominal fat weight and plasma leptin, and insulin levels in response to stress without affecting HOMA-IR index and islets' insulin secretion. CONCLUSIONS: High proportion of unsaturated fat may not lead to deleterious metabolic responses; however combined with chronic stress has a synergistic and adverse effect on visceral adiposity and results in elevated plasma leptin.

Maternal high-fat diet intensifies the metabolic response to stress in male rat offspring.

BACKGROUND: The mother's consumption of high-fat food can affect glucose metabolism and the hypothalamic-pituitary-adrenal axis responsiveness in the offspring and potentially affect the metabolic responses to stress as well. This study examines the effect of maternal high-fat diet on the expression of pancreatic glucose transporter 2 and the secretion of insulin in response to stress in offspring. METHODS: Female rats were randomly divided into normal and high-fat diet groups and were fed in accordance with their given diets from pre-pregnancy to the end of lactation. The offspring were divided into control (NC and HFC) and stress (NS and HFS) groups based on their mothers' diet and exposure to stress in adulthood. After the two-week stress induction period was over, an intraperitoneal glucose tolerance test (IPGTT) was performed and plasma glucose and insulin levels were assessed. The pancreas was then removed for measuring insulin secretion from the isolated islets as well as glucose transporter 2 mRNA expression and protein levels. RESULTS: According to the results obtained, plasma corticosterone concentrations increased significantly on days 1 and 14 of the stress induction period and were lower on the last day compared to on the first day. In both the NS and HFS groups, stress reduced plasma insulin concentration in the IPGTT without changing the plasma glucose concentration, suggesting an increased insulin sensitivity in the NS and HFS groups, although more markedly in the latter. Stress reduced insulin secretion (at high glucose concentrations) and increased glucose transporter 2 mRNA and protein expression, especially in the HFS group. CONCLUSION: Mothers' high-fat diet appears to intensify the stress response by changing the programming of the neuroendocrine system in the offspring.