Fasting-induced Decrease Research Articles

Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting

BackgroundThe activation of the hypothalamic–pituitary–adrenal (HPA) axis is essential for metabolic adaptation in response to fasting. However, the neurocircuitry connecting changes in the peripheral energy stores to the activity of hypothalamic paraventricular corticotrophin-releasing factor (CRFPVN) neurons, the master controller of the HPA axis activity, is not completely understood. Our main goal was to determine if hypothalamic arcuate nucleus (ARC) POMC and AgRP neurons can communicate fasting-induced changes in peripheral energy stores, associated to a fall in plasma leptin levels, to CRFPVN neurons to modulate the HPA axis activity in mice.ResultsWe observed increased plasma corticosterone levels associate with increased CRFPVN mRNA expression and increased CRFPVN neuronal activity in 36 h fasted mice. These responses were associated with a fall in plasma leptin levels and changes in the mRNA expression of Agrp and Pomc in the ARC. Fasting-induced decrease in plasma leptin partially modulated these responses through a change in the activity of ARC neurons. The chemogenetic activation of POMCARC by DREADDs did not affect fasting-induced activation of the HPA axis. DREADDs inhibition of AgRPARC neurons reduced the content of CRFPVN and increased its accumulation in the median eminence but had no effect on corticosterone secretion induced by fasting.ConclusionOur data indicate that AgRPARC neurons are part of the neurocircuitry involved in the coupling of PVNCRF activity to changes in peripheral energy stores induced by prolonged fasting.

Effects of Short-term Fasting on Ghrelin/GH/IGF-1 Axis in Healthy Humans: The Role of Ghrelin in the Thrifty Phenotype.

A greater decrease in 24-hour energy expenditure (24hEE) during short-term fasting is indicative of a thrifty phenotype. As ghrelin and the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis are implicated in the regulation of energy intake and metabolism, we investigated whether ghrelin, GH, and IGF-1 concentrations mediate the fasting-induced decrease in 24hEE that characterizes thriftiness. In 47 healthy individuals, 24hEE was measured in a whole-room indirect calorimeter both during 24-hour eucaloric and fasting conditions. Plasma total ghrelin, GH, and IGF-1 concentrations were measured by enzyme-linked immunosorbent assay after an overnight fast the morning before and after each 24-hour session. During 24-hour fasting, on average 24hEE decreased by 8.0% (P < .001), GH increased by ~5-fold (P < .001), whereas ghrelin (mean +23 pg/mL) and IGF-1 were unchanged (both P ≥ .19) despite a large interindividual variability in ghrelin change (SD 150 pg/mL). Greater fasting-induced increase in ghrelin was associated with a greater decrease in 24hEE during 24-hour fasting (r = -0.42, P = .003), such that individuals who increased ghrelin by 200 pg/mL showed an average decrease in 24hEE by 55 kcal/day. Short-term fasting induced selective changes in the ghrelin/GH/IGF-1 axis, specifically a ghrelin-independent GH hypersecretion that did not translate into increased IGF-1 concentrations. Greater increase in ghrelin after 24-hour fasting was associated with greater decrease in 24hEE, indicating ghrelin as a novel biomarker of increased energy efficiency of the thrifty phenotype.

Glycemic management via fasting-induced decrease in blood glucose concentration: A protective intervention against COVID-19?

According to the literature, uncontrolled glycemia can be a strong predictor of severe morbidity and mortality in different types of viral infections. Hyperglycemia can make the condition worse in diabetic and nondiabetic patients infected with sever acute respiratory syndrome 2 (SARS-CoV-2). Therefore, maintaining blood glucose levels low (within the safe range of 70-100 mg/ mg/dl) seems to be beneficial in our battle against Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2.

Changes in bone density and bone quality caused by single fasting for 96 hours in rats.

BackgroundYoung women occasionally engage in dietary restrictions accompanied by fasting for the purpose of losing weight, but such restrictions have various effects on body functions. The recent increase in the number of people suffering from osteoporosis has become a major social problem mainly in industrialized countries.Therefore, we think it is important to understand the effects of fasting on bone vulnerability, especially to bone quality.MethodsAnimals used male Wister rats weighing 130 g (6 weeks of age), and were divided into a control group (n = 5) and a fasting group (n = 6). The experimental period was 14 days, the control group had ad libitum food throughout the experimental period, the fasted group was fasted for 4 days, and than, had ad libitum food for 10 days. In this study, parameters related to bone fragility due to three-dimensional bone architecture were determined on Contrast enhanced micro-CT images of the lumbar spine and were used as a method for the evaluation of bone quality. In addition, a time-course observation of each individual was carried out during the fasting period and later upon resuming food intake. Cross-sectional images of all vertebrae were obtained from radiographic computed tomography and were analyzed by using Latheta software ver. 3.0 (Hitachi-Aloka Medical, Nagasaki, Japan). The region of interest that was misrecognized in each cross-sectional image was made consistent with the anatomical structure by carrying out corrections manually and by identifying the cortical bone areas and cancellous bone areas.ResultsOur findings showed that while single fasting for 96 h did not cause any major change in the macroscopic morphology of bone, it caused a marked decrease in bone density. In addition, the minimum cross-sectional moment, which indicated the “strength against bending” as well as the polar moment that indicated the “strength against torsion” were both lower than in non-fasted rats. Further, after resumption of feeding, bone mineral content in the fasting group recovered rapidly and starting at day 4 after resumption of feeding, there was no difference with the control group. On the other hand, the values of the minimum cross-sectional moment and polar moment did not recover, and the difference with the control group increased during the feeding period.DiscussionOn the basis of this study, the authors estimate that the fasting-induced decrease in bone minimum cross-sectional moment and polar moment may have been due to changes affecting some factors involved in bone quality, and thus could be useful as a parameter in future studies aimed at elucidating bone quality. At least, in the case where bone change accompanied with a change in macroscopic distribution of mineral components occurs, the values of minimum cross-sectional moment and polar moment are considered to be bone parameters that will provide valuable information to elucidate bone quality.

First evidence of nocturnin in fish: two isoforms in goldfish differentially regulated by feeding.

Nocturnin (NOC) is a unique deadenylase with robust rhythmic expression involved in the regulation of metabolic processes in mammals. Currently, the possible presence of NOC in fish is unknown. This report aimed to identify NOC in a fish model, the goldfish ( Carassius auratus), and to study the possible regulation of its expression by feeding. Two partial-length cDNAs of 293 and 223 bp, named nocturnin-a ( noc-a) and nocturnin-b ( noc-b), were identified and found to be highly conserved among vertebrates. Both mRNAs show a similar widespread distribution in central and peripheral tissues, with higher levels detected for noc-a compared with noc-b. The periprandial expression profile revealed that noc-a mRNAs rise sharply after a meal in hypothalamus, intestinal bulb, and liver, whereas almost no changes were observed for noc-b. Food deprivation was found to exert opposite effects on the expression of both NOCs (generally inhibitory for noc-a, and stimulatory for noc-b) in the three mentioned tissues. A single meal after a 48-h food deprivation period reversed (totally or partially) the fasting-induced decreases in noc-a transcripts in all studied tissues and the increases in noc-b expression in the intestinal bulb. Together, this study offers the first report of NOC in fish and shows a high dependence of its expression on feeding and nutritional status. The differential responses to feeding of the two NOCs raise the possibility that they might be underlying different physiological mechanisms (e.g., food intake, lipid mobilization, energy homeostasis) in fish.

Effect of growth hormone on steroid concentrations and mRNA expression of their receptor, and selected egg-specific protein genes in the chicken oviduct during pause in laying induced by fasting

This study was undertaken to examine the effect of growth hormone (GH) treatment during pause in laying on (1) the concentration of steroids in blood plasma and oviduct tissues, (2) the expression of mRNA of steroid receptors, and (3) the mRNA expression of selected egg-specific proteins in the chicken oviduct. A pause in egg laying was induced by food deprivation for 5 d, followed by feeding every other day, and then feeding daily from Day 10 onward. Birds were divided into three groups: control (n = 18) fed ad libitum, subjected to pause in laying (n = 18), and subjected to pause in laying and injected every day with 200 μg/kg BW of chicken GH (chGH; n = 18). The oviduct was isolated from hens of each group on Days 6 (when the oviduct was regressed), 13 (during oviduct recrudescence), and 17 or 20 (rejuvenated oviduct) of the experiment. Fasting caused a decrease in plasma concentrations of progesterone (P4), testosterone, and estradiol on Day 6 and a reduction in tissue concentrations of these steroids on Days 6 and 13. Fasting also caused an increased relative expression of estrogen receptor α and β (ERα, ERβ) and progesterone receptor (PR) in the magnum and shell gland on Day 6, increased ERα and PR in the magnum on Days 13 and 17 or 20, and increased androgen receptor (AR) mRNA in the magnum on Days 6 and 13 and in the shell gland on Day 13. A fasting-induced elevation in ovocalyxin-36 mRNA expression on Day 6 and a decrease in avidin mRNA on Days 6 and 13 and in ovocleidin-116 on Day 13 were also observed (P < 0.05 to P < 0.001). Administration of chGH abolished the fasting-induced decrease in the concentration of steroids in plasma and tissues. Furthermore, chGH enhanced the effect of fasting on mRNA expression of PR, ERα, and avidin in the magnum on Day 6, and ERα in the shell gland on Day 13. The gene expression of ovalbumin on Days 6 and 13, ovocalyxin-36 and ovocleidin-116 on Day 6 was decreased in chGH-treated chickens. In contrast, the expression of ovalbumin on Day 17 or 20 was increased (P < 0.05 to P < 0.001). The results obtained indicate that, by alterations in the concentration of steroid hormones and their receptor expression in the chicken oviduct, GH determines the rate of regression and rejuvenation of this organ during molting. Moreover, changes in the expression of selected egg proteins indicate that GH might be the regulator of the secretory activity of the hen oviduct.

The 5′-Deiodinases Are Not Essential for the Fasting-Induced Decrease in Circulating Thyroid Hormone Levels in Male Mice: Possible Roles for the Type 3 Deiodinase and Tissue Sequestration of Hormone

Fasting in rodents is characterized by decreases in serum T4 and T3 levels but no compensatory increase in serum TSH level. The types 1 and 2 deiodinases (D1 and D2) are postulated to play key roles in mediating these changes. However, serum T4 and T3 levels in fasted 5'-deiodinase-deficient mice decreased by at least the same percentage as that observed in wild-type mice, whereas serum TSH level was unaffected. D3 activity was increased in kidney, muscle, and liver up to 4-fold during fasting, and the mean serum rT3 level was increased 3-fold in fasted D1-deficient mice, compared with fed animals. In wild-type mice, the tissue contents of T4 and T3 in liver, kidney, and muscle were unchanged or increased in fasted animals, and after the administration of [(125)I]T4 or [(125)I]T3, the radioactive content in the majority of tissues from fasted mice was increased 2- or 4-fold, respectively. These findings suggest that the observed fasting-induced reductions in the circulating T3 and T4 levels are mediated in part by increased D3 activity and by the sequestration of thyroid hormone and their metabolites in tissues. Studies performed in D3-deficient mice demonstrating a blunting of the fasting-induced decrease in serum T4 and T3 levels were consistent with this thesis. Thus, the systemic changes in thyroid hormone economy as a result of acute food deprivation are not dependent on the D1 or D2 but are mediated in part by sequestration of T4 and T3 in tissues and their enhanced metabolism by the D3.

Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver

Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.

Efficacy of oral potassium chloride administration in treating lactating dairy cows with experimentally induced hypokalemia, hypochloremia, and alkalemia

Hypokalemia occurs commonly in lactating dairy cows. The objectives of this study were to determine (1) whether a 24-h oral KCl dose of 0.4g/kg of body weight (BW) was effective and safe in hypokalemic cattle; (2) whether potassium was best administered as 2 large doses or multiple smaller doses over a 24-h period; and (3) the effect of oral KCl administration on plasma Mg concentration and urine Mg excretion in fasted lactating dairy cattle. Plasma K and Cl concentrations were decreased, and blood pH increased, in 15 lactating Holstein-Friesian cows by administering 2 intramuscular (i.m.) 10-mg injections of isoflupredone acetate 24h apart followed by 2 i.m. injections of furosemide (1mg/kg of BW) 8h apart and by decreasing feed intake. Cows were randomly assigned to 1 of 3 treatment groups with 5 cows/group: untreated control (group C); oral administration of KCl at 0.05g/kg of BW 8 times at 3-h intervals (group K3); and oral administration of KCl at 0.2g/kg of BW twice at 12-h intervals (group K12). A 24-h KCl dose rate of 0.4g/kg of BW increased plasma and milk K concentration and plasma Cl concentration, and corrected the metabolic alkalosis and alkalemia, with no clinically significant difference between 2 large doses (group K12) or multiple small doses (group K3) of KCl over 24 h. Oral KCl administration decreased peripheral fat mobilization in cattle with experimentally induced hypokalemia, as measured by changes in plasma nonesterified fatty acid concentration, and slightly augmented the fasting-induced decrease in plasma Mg concentration. Our findings support recommendations for a 24-h oral KCl dose of 0.4g/kg of BW for treating moderately hypokalemic cattle. Additional Mg may need to be administered to inappetant lactating dairy cattle being treated with oral KCl to minimize K-induced decreases in magnesium absorption.

SIRT1 regulates adaptive response of the growth hormone--insulin-like growth factor-I axis under fasting conditions in liver

Adaptation under fasting conditions is critical for survival in animals. Sirtuin 1 (SIRT1), a protein deacetylase, plays an essential role in adaptive metabolic and endocrine responses under fasting conditions by modifying the acetylation status of various proteins. Fasting induces growth hormone (GH) resistance in the liver, leading to decreased serum insulin-like growth factor-I (IGF-I) levels as an endocrine adaptation for malnutrition; however, the underlying mechanisms of this action remain to be fully elucidated. Here we report that in vivo knockdown of SIRT1 in the liver restored the fasting-induced decrease in serum IGF-I levels and enhanced the GH-dependent increase in IGF-I levels, indicating that SIRT1 negatively regulates GH-dependent IGF-I production in the liver. In vitro analysis using hepatocytes demonstrated that SIRT1 suppresses GH-dependent IGF-I expression, accompanied by decreased tyrosine phosphorylation on signal transducer and activator of transcription (STAT) 5. GST pull-down assays revealed that SIRT1 interacts directly with STAT5. When the lysine residues adjacent to the SH2 domain of STAT5 were mutated, STAT5 acetylation decreased concomitant with a decrease in its transcriptional activity. Knockdown of SIRT1 enhanced the acetylation and GH-induced tyrosine phosphorylation of STAT5, as well as the GH-induced interaction of the GH receptor with STAT5. These data indicate that SIRT1 negatively regulates GH-induced STAT5 phosphorylation and IGF-I production via deacetylation of STAT5 in the liver. In addition, our findings explain the underlying mechanisms of GH resistance under fasting conditions, which is a known element of endocrine adaptation during fasting.

Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.

Moderate Long-Term Modulation of Neuropeptide Y in Hypothalamic Arcuate Nucleus Induces Energy Balance Alterations in Adult Rats

Neuropeptide Y (NPY) produced by arcuate nucleus (ARC) neurons has a strong orexigenic effect on target neurons. Hypothalamic NPY levels undergo wide-ranging oscillations during the circadian cycle and in response to fasting and peripheral hormones (from 0.25 to 10-fold change). The aim of the present study was to evaluate the impact of a moderate long-term modulation of NPY within the ARC neurons on food consumption, body weight gain and hypothalamic neuropeptides. We achieved a physiological overexpression (3.6-fold increase) and down-regulation (0.5-fold decrease) of NPY in the rat ARC by injection of AAV vectors expressing NPY and synthetic microRNA that target the NPY, respectively. Our work shows that a moderate overexpression of NPY was sufficient to induce diurnal over-feeding, sustained body weight gain and severe obesity in adult rats. Additionally, the circulating levels of leptin were elevated but the immunoreactivity (ir) of ARC neuropeptides was not in accordance (POMC-ir was unchanged and AGRP-ir increased), suggesting a disruption in the ability of ARC neurons to response to peripheral metabolic alterations. Furthermore, a dysfunction in adipocytes phenotype was observed in these obese rats. In addition, moderate down-regulation of NPY did not affect basal feeding or normal body weight gain but the response to food deprivation was compromised since fasting-induced hyperphagia was inhibited and fasting-induced decrease in locomotor activity was absent.These results highlight the importance of the physiological ARC NPY levels oscillations on feeding regulation, fasting response and body weight preservation, and are important for the design of therapeutic interventions for obesity that include the NPY.

Alstonine as an Antipsychotic: Effects on Brain Amines and Metabolic Changes

Managing schizophrenia has never been a trivial matter. Furthermore, while classical antipsychotics induce extrapyramidal side effects and hyperprolactinaemia, atypical antipsychotics lead to diabetes, hyperlipidaemia, and weight gain. Moreover, even with newer drugs, a sizable proportion of patients do not show significant improvement. Alstonine is an indole alkaloid identified as the major component of a plant-based remedy used in Nigeria to treat the mentally ill. Alstonine presents a clear antipsychotic profile in rodents, apparently with differential effects in distinct dopaminergic pathways. The aim of this study was to complement the antipsychotic profile of alstonine, verifying its effects on brain amines in mouse frontal cortex and striatum. Additionally, we examined if alstonine induces some hormonal and metabolic changes common to antipsychotics. HPLC data reveal that alstonine increases serotonergic transmission and increases intraneuronal dopamine catabolism. In relation to possible side effects, preliminary data suggest that alstonine does not affect prolactin levels, does not induce gains in body weight, but prevents the expected fasting-induced decrease in glucose levels. Overall, this study reinforces the proposal that alstonine is a potential innovative antipsychotic, and that a comprehensive understanding of its neurochemical basis may open new avenues to developing newer antipsychotic medications.

Intermittent fasting modulation of the diabetic syndrome in sand rats. III. Post-mortem investigations

The present report concerns several post-mortem variables examined in sand rats that were either maintained on a vegetal diet (control animals) or exposed first during a 20-day transition period to a mixed diet consisting of a fixed amount of a hypercaloric food and decreasing amounts of the vegetal food and then to a 30-day experimental period of exposure to the hypercaloric food. During the latter period, all animals were either given free access to food or fasting daily for 15 h, i.e. from 5.00 p.m. to 8.00 a.m. The body weight, liver wet weight, pancreas wet weight, plasma glucose and haemoglobin A1c concentration, plasma insulin concentration, insulinogenic index, insulin resistance HOMA, plasma cholesterol and triglyceride concentration, liver triglyceride and phospholipid content were all measured. Pancreatic islet (insulin, GLUT2) and liver (lipid droplets) histology were also examined. The main findings consisted in a lower body weight of fasting than non-fasting animals, a higher liver weight in non-diabetic and diabetic rats than in control non-fasting (but not so in fasting) animals, a decrease of pancreas weight in non-diabetic and diabetic as distinct from control animals, a fasting-induced decrease in plasma glucose, plasma insulin and insulin resistance HOMA, plasma cholesterol and triglyceride concentration and triglyceride liver content.

Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

Postprandial cellular glucose uptake is dependent on an insulin-signaling cascade in muscle and adipose tissue, resulting in the translocation of the insulin-dependent glucose transporter 4 (Glut4) into the plasma membrane. Additionally, extended food deprivation is characterized by suppressed insulin signaling and decreased Glut4 expression. Northern elephant seals are adapted to prolonged fasts characterized by high levels of plasma glucose. To address the hypothesis that the fasting-induced decrease in insulin is associated with reduced insulin signaling in prolonged fasted seals, we compared the adipose protein levels of the cellular insulin-signaling pathway, Glut4 and plasma glucose, insulin, cortisol, and adiponectin concentrations between Early (n = 9; 2-3 wks postweaning) and Late (n = 8; 6-8 wks postweaning) fasted seals. Plasma adiponectin (230 ± 13 vs. 177 ± 11 ng/ml), insulin (2.7 ± 0.4 vs. 1.0 ± 0.1 μU/ml), and glucose (9.8 ± 0.5 vs. 8.0 ± 0.3 mM) decreased, while cortisol (124 ± 6 vs. 257 ± 30 nM) doubled with fasting. Glut4 increased (31%) with fasting despite the significant decreases in the cellular content of phosphatidylinositol 3-kinase as well as phosphorylated insulin receptor, insulin receptor substrate-1, and Akt2. Increased Glut4 may have contributed to the decrease in plasma glucose, but the decrease in insulin and insulin signaling suggests that Glut4 is not insulin-dependent in adipose tissue during prolonged fasting in elephant seals. The reduction of plasma glucose independent of insulin may make these animals an ideal model for the study of insulin resistance.

The role of somatostatin receptor type 4 in the adaptation to fasting

Event Abstract Back to Event The role of somatostatin receptor type 4 in the adaptation to fasting Zsófia Barcza1, Erika Pétervári1*, Zsuzsanna Helyes2, Miklós Székely1 and Zoltán Szelényi1 1 University of Pécs, Department of Pathophysiology and Gerontology, Medical School, Hungary 2 University of Pécs, Department of Pharmacology and Pharmacotherapy, Medical School, Hungary Somatostatin is a well-known somatotrop hormone inhibitor, but the peptide is ubiquitous in the body with variable effects from inhibition of gastrointestinal (GI) motility and absorption to suppression of neurogenic inflammation and locomotor activity, etc. The five subtypes of somatostatin receptors (SSTR1-5) are expressed in a tissue specific manner and play different roles. SSTR4 has been proven to be devoid of endocrine activity, while being an important regulator of inflammatory processes. Previous studies indicated a suppressor function of SSTR4 on capsaicin-sensitive, transient receptor potential vanilloid 1 (TRPV1) receptors, that were also implicated in the regulation of energy homeostasis according to our data. Now, we aimed to investigate the possible role of SSTR4 in energy homeostasis and adaptation to fasting. The effects of a 48-h fasting was studied on food intake (FI) and body weight (BW) in 4 months old C57BL6 (wild type, WT) and SSTR4 knock-out (KO) mice. In a biotelemetric system core temperature (Tc) and locomotor activity (ACT) were also monitored. Under control conditions, daily FI, BW development, circadian Tc and ACT values did not differ in the two groups. Although the fasting-induced decrease in BW was similar in both groups, Tc of KO mice showed a significantly larger fall. On the other hand, ACT of the KO animals increased significantly compared with WT mice. Upon re-feeding, FI of the KO group was smaller. Our results suggest that SSTR4 activity interferes with adaptation to fasting. Improved adaptation in KO animals was indicated by deeper Tc, enhanced Act (presumably search for food) and diminished re-feeding, however, KO mice lost comparable amounts of BW as WT animals. The better metabolic adaptation may have been counterbalanced by increased activity and GI motility. Further investigations should be carried out concerning the role of SSTR4 in energy homeostasis. OTKA T62598, GVOP-3.2.1.-2004-0271/3.0. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Homeostatic and neuroendocrine systems Citation: Barcza Z, Pétervári E, Helyes Z, Székely M and Szelényi Z (2010). The role of somatostatin receptor type 4 in the adaptation to fasting. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00079 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Apr 2010; Published Online: 21 Apr 2010. * Correspondence: Erika Pétervári, University of Pécs, Department of Pathophysiology and Gerontology, Medical School, Pécs, Hungary, erika.petervari@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Zsófia Barcza Erika Pétervári Zsuzsanna Helyes Miklós Székely Zoltán Szelényi Google Zsófia Barcza Erika Pétervári Zsuzsanna Helyes Miklós Székely Zoltán Szelényi Google Scholar Zsófia Barcza Erika Pétervári Zsuzsanna Helyes Miklós Székely Zoltán Szelényi PubMed Zsófia Barcza Erika Pétervári Zsuzsanna Helyes Miklós Székely Zoltán Szelényi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Abstract: 67 CHARACTERISTICS OF CIRCULATING VLDL RESULTING FROM INSULIN RESISTANCE AND FATTY LIVER

Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.

α2-AMPK activity is not essential for an increase in fatty acid oxidation during low-intensity exercise

A single bout of exercise increases glucose uptake and fatty acid oxidation in skeletal muscle, with a corresponding activation of AMP-activated protein kinase (AMPK). While the exercise-induced increase in glucose uptake is partly due to activation of AMPK, it is unclear whether the increase of fatty acid oxidation is dependent on activation of AMPK. To examine this, transgenic mice were produced expressing a dominant-negative (DN) mutant of alpha(1)-AMPK (alpha(1)-AMPK-DN) in skeletal muscle and subjected to treadmill running. alpha(1)-AMPK-DN mice exhibited a 50% reduction in alpha(1)-AMPK activity and almost complete loss of alpha(2)-AMPK activity in skeletal muscle compared with wild-type littermates (WT). The fasting-induced decrease in respiratory quotient (RQ) ratio and reduced body weight were similar in both groups. In contrast with WT mice, alpha(1)-AMPK-DN mice could not perform high-intensity (30 m/min) treadmill exercise, although their response to low-intensity (10 m/min) treadmill exercise was not compromised. Changes in oxygen consumption and the RQ ratio during sedentary and low-intensity exercise were not different between alpha(1)-AMPK-DN and WT. Importantly, at low-intensity exercise, increased fatty acid oxidation in response to exercise in soleus (type I, slow twitch muscle) or extensor digitorum longus muscle (type II, fast twitch muscle) was not impaired in alpha(1)-AMPK-DN mice, indicating that alpha(1)-AMPK-DN mice utilize fatty acid in the same manner as WT mice during low-intensity exercise. These findings suggest that an increased alpha(2)-AMPK activity is not essential for increased skeletal muscle fatty acid oxidation during endurance exercise.

Metabolic environment in substantia nigra reticulata is critical for the expression and control of hypoglycemia-induced seizures.

Seizures represent a common and serious complication of hypoglycemia. Here we studied mechanisms of control of hypoglycemic seizures induced by insulin injection in fasted and nonfasted rats. We demonstrate that fasting predisposes rats to more rapid and consistent development of hypoglycemic seizures. However, the fasting-induced decrease in baseline blood glucose concentration cannot account for the earlier onset of seizures in fasted versus nonfasted rats. Data obtained with c-Fos immunohistochemistry and [14C]2-deoxyglucose uptake implicate a prominent involvement of the substantia nigra reticulata (SNR) among other structures in the hypoglycemic seizure control. This is supported by data showing that fasting decreases the SNR expression of K(ATP) channels, which link metabolism with activity, and is further confirmed with microinfusions of K(ATP) channel agonist and antagonist. Data obtained with whole-cell and perforated patch recordings from SNR neurons in slices in vitro demonstrate that both presynaptic and postsynaptic K(ATP) channels participate in the failure of the SNR to control hypoglycemic seizures. The results suggest that fasting and insulin-induced hypoglycemia can lead to impairment in the function of the SNR, leading thus to hypoglycemic seizures.

O2-05-08: Protein O-Glcnacylation: A novel mechanism involved in Alzheimer's disease

Neurofibrillary degeneration plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and correlates directly with dementia of affected individuals. However, the molecular mechanism(s) leading to neurofibrillary degeneration is not well understood. Microtubule-associated protein tau and neurofilaments are the key proteins involved in neurofibrillary degeneration and are post-translationally modified by both O-GlcNAcylation (a unique type of O-glycosylation of protein with β-N-acetyl-glucosamine, GlcNAc) and phosphorylation. The role of O-GlcNAcylation in phosphorylation of tau and neurofilaments were studied in vitro, in cultured cells, in metabolically active rat brain slices, and in vivo. We found that O-GlcNAcylation of tau and neurofilaments regulates their phosphorylation inversely. In cell cultures and in metabolically active rat brain slices, elevation of O-GlcNAcylation induced decreased phosphorylation of tau and neurofilaments at multiple phosphorylation sites, whereas reduction of O-GlcNAcylation resulted in hyperphosphorylation of these proteins. In vivo, fasting-induced decrease in glucose uptake/metabolism caused down-regulation of O-GlcNAcylation and upregulation of phosphorylation of tau and neurofilaments in the mouse brain. Hippocampus was found to be more vulnerable than cerebral cortex to the fasting-induced alteration of tau O-GlcNAcylation and phosphorylation, which is consistent with the differential susceptibility of various brain regions in AD. Re-feeding of the mice reversed the dysregulation of both O-GlcNAcylation and phosphorylation of tau. More importantly, the level of O-GlcNAcylation of tau and neurofilaments was decreased in AD brain, and this decrease was correlated negatively to the level of phosphorylation of these two proteins. The major glucose transporters (GLUTs) responsible for glucose uptake into neurons from blood stream, GLUT1 and GLUT3, were decreased in AD brain. This decrease correlated to the decrease in protein O-GlcNAcylation, to the hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. On the basis of our findings, we propose a novel mechanism by which the impaired brain glucose uptake/metabolism causes a decrease in tau O-GlcNAcylation, leading to Alzheimer neurofibrillary degeneration by facilitating abnormal hyperphosphorylation of tau and neurofilaments.