The Antiepileptic Ketogenic Diet Alters Hippocampal Transporter Levels and Reduces Adiposity in Aged Rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Hernandez AR
PROVIDER: S-EPMC5861916 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background and purposeIncidence and severity of obesity are increasing worldwide, however, efficient and safe pharmacological treatments are not yet available. Certain MAO inhibitors reduce body weight, although their effects on metabolic parameters have not been investigated. Here, we have assessed effects of a widely used, selective MAO-B inhibitor, selegiline, on metabolic parameters in a rat model of diet-induced obesity.Experimental approachMale Long-Evans rats were given control (CON) or a high-fat (20%), high-sucrose (15%) diet (HFS) for 25 weeks. From week 16, animals were injected s.c. with 0.25 mg·kg-1 selegiline (CON + S and HFS + S) or vehicle (CON, HFS) once daily. Whole body, subcutaneous and visceral fat was measured by CT, and glucose and insulin tolerance were tested. Expression of glucose transporters and chemokines was assessed by quantitative RT-PCR.Key resultsSelegiline decreased whole body fat, subcutaneous- and visceral adiposity, measured by CT and epididymal fat weight in the HFS group, compared with HFS placebo animals, without influencing body weight. Oral glucose tolerance and insulin tolerance tests showed impaired glucose homeostasis in HFS and HFS + S groups, although insulin levels in plasma and pancreas were unchanged. HFS induced expression of Srebp-1c, Glut1 and Ccl3 in adipose tissue, which were alleviated by selegiline.Conclusions and implicationsSelegiline reduced adiposity, changes in adipose tissue energy metabolism and adipose inflammation induced by HFS diet without affecting the increased body weight, impairment of glucose homeostasis, or behaviour. These results suggest that selegiline could mitigate harmful effects of visceral adiposity.
| S-EPMC6109222 | biostudies-literature
Project description:Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here, we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral--CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high-calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines.
| S-EPMC2694409 | biostudies-literature
Project description:Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterised by deficient glucose transport over the blood-brain barrier and reduced glucose availability in the brain. This causes epilepsy, movement disorders, and cognitive impairment. Treatment with ketogenic diet provides ketones as alternative energy source. However, not all GLUT1DS patients are on dietary treatment (worldwide registry: 77/181 [43%] of patients). The current 25-year experience allows evaluation of effects and tolerability of dietary treatment for GLUT1DS. To this end, literature was searched up to January 2019 for individual case reports and series reporting (side) effects of dietary treatment for GLUT1DS. Upon aggregation of data for analysis, we identified 270 GLUT1DS patients with dietary treatment with a mean follow-up of 53?months. Epilepsy improved for 83% of 230 patients and remained unchanged for 17%, movement disorders improved for 82% of 127 patients and remained unchanged for 17%, and cognition improved for 59% of 58 patients and remained stable for 40%. Effects on epilepsy were seen within days/weeks and were most pronounced in patients with early treatment initiation. Effects on movement disorders were noticed within months and were strongest in patients with higher cerebrospinal fluid-to-blood glucose ratio. Although side effects were minimal, 18% of 270 patients reported poor compliance. In individual patients, symptoms deteriorated upon low ketosis, poor compliance, or treatment discontinuation. Based on the good tolerability and strong favourable effect of dietary treatment on GLUT1DS symptoms, we advocate dietary treatment in all GLUT1DS patients and prompt diagnosis or screening to allow early treatment.
| S-EPMC7078900 | biostudies-literature
Project description:Background/objectivesLow levels of orexin are associated with obesity and reduced physical activity in humans and animals.Subjects/methodsDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) selectively activated orexin neurons in mouse lateral hypothalamus (LH) to measure effects on spontaneous physical activity (SPA). DREADD targeting was achieved by stereotaxic injection of AAV vectors into caudal lateral LH of heterozygous orexin-Cre or C57/B6J mice. In one set of studies, excitation of orexin neurons was examined (virus: AAV2-EF1a-DIO-hM3Dq-mCherry), and test sessions began 3-4 h after light cycle onset. In a study examining the inhibition of orexin neurons (virus: AAV2-hSyn-DIO-hM4Di-mCherry), testing began 15 min prior to dark cycle onset. Clozapine n-oxide (CNO; 1 or 5 mg/kg) or saline was injected intraperitoneally and time spent moving in open field chambers was recorded for 2 h. Follow-up studies in separate mouse cohorts quantified SPA in parallel with changes in energy expenditure (EE) and chow intake using indirect calorimetry chambers (SableSystem™). Following acclimation, testing sessions (saline and/or CNO) took place over the course of ~1 week, with injections administered every day. Changes in SPA, EE, chow intake, fecal boli, and body composition (EchoMRI™) were measured. Additional mice cohorts were fed a high-fat diet (HFD) and injected with CNO daily up to 10 days to assess the potential for orexin activation to prevent diet-induced obesity.ResultsActivation of orexin resulted in increases in SPA in male and female mice, and was accompanied by increases in energy expenditure without changes in overall chow intake. When orexin activation occurred in the context of high fat diet, weight gain and adiposity were significantly attenuated. SPA was decreased when DREADDs were used to inhibit orexin activity.ConclusionThese results demonstrate that orexin neurons play a critical role in mediating physical activity and suggest a novel therapeutic target for treating obesity.
| S-EPMC5962366 | biostudies-literature
Project description:BackgroundKetogenic diet (KD) has been proposed to be an effective lifestyle intervention in metabolic syndrome. However, the effects of KD on cardiac remodeling have not been investigated. Our aim was to investigate the effects and the underling mechanisms of KD on cardiac remodeling in spontaneously hypertensive rats (SHRs).Methods10-week-old spontaneously hypertensive rats were subjected to normal diet or ketogenic diet for 4 weeks. Then, their blood pressure and cardiac remodeling were assessed. Cardiac fibroblasts were isolated from 1- to 3-day-old neonatal pups. The cells were then cultured with ketone body with or without TGF-β to investigate the mechanism in vitro.Results4 weeks of KD feeding aggravated interstitial fibrosis and cardiac remodeling in SHRs. More interestingly, ketogenic diet feeding increased the activity of mammalian target of rapamyoin (mTOR) complex 2 pathway in the heart of SHRs. In addition, β-hydroxybutyrate strengthened the progression of TGF-β-induced fibrosis in isolated cardiac fibroblasts. mTOR inhibition reversed this effect, indicating that ketone body contributes to cardiac fibroblasts via mTOR pathway.ConclusionsThese data suggest that ketogenic diet may lead to adverse effects on the remodeling in the hypertensive heart, and they underscore the necessity to fully evaluate its reliability before clinical use.
| S-EPMC7586698 | biostudies-literature
Project description:Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.
| S-EPMC5605815 | biostudies-literature
Project description:BackgroundPrebiotic dietary fibers change the intestinal microbiome favorably and provide a health benefit to the host.ObjectivesPolylactose is a novel fiber, synthesized by extrusion of lactose. We evaluated its prebiotic activity by determining its fermentability, effect on the microbiota, and effects on adiposity and liver lipids in a diet-induced obesity animal model.MethodsMale Wistar rats (4-5 wk old) were fed normal-fat (NF, 25% fat energy) or high-fat (HF, 51% fat energy) diets containing different fibers (6% fiber of interest and 3% cellulose, by weight), including cellulose (NFC and HFC, negative and positive controls, respectively), polylactose (HFPL), lactose matched to residual lactose in the HFPL diet, and 2 established prebiotic fibers: polydextrose (HFPD) and fructooligosaccharide (HFFOS). After 10 wk of feeding, organs were harvested and cecal contents collected.ResultsHFPL animals had greater cecum weight (3 times greater than HFC) and lower cecal pH (∼1 pH unit lower than HFC) than all other groups, suggesting that polylactose is more fermentable than other prebiotic fibers (HFPD, HFFOS; P < 0.05). HFPL animals also had increased taxonomic abundance of the probiotic species Bifidobacterium in the cecum relative to all other groups (P < 0.05). Epididymal fat pad weight was significantly decreased in the HFPL group (29% decrease compared with HFC) compared with all other HF groups (P < 0.05) and did not differ from the NFC group. Liver lipids and cholesterol were reduced in HFPL animals when compared with HFC animals (P < 0.05).ConclusionsPolylactose is a fermentable fiber that elicits a beneficial change in the gut microbiota as well as reducing adiposity in rats fed HF diets. These effects of polylactose were greater than those of 2 established prebiotics, fructooligosaccharide and polydextrose, suggesting that polylactose is a potent prebiotic.
| S-EPMC8096245 | biostudies-literature
Project description:IntroductionDiminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function.ObjectivesThis study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD).MethodsEight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested.ResultsDHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aβ burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein.ConclusionDHA improves cognitive function by enhancing hippocampal insulin sensitivity.
| S-EPMC10006543 | biostudies-literature
Project description:As the global population ages, and rates of dementia rise, understanding lifestyle factors that play a role in the development and acceleration of cognitive decline is vital to creating therapies and recommendations to improve quality of later life. Obesity has been shown to increase risk for dementia. However, the specific mechanisms for obesity-induced cognitive decline remain unclear. One potential contributor to diet-induced cognitive changes is neuroinflammation. Furthermore, a source of diet-induced inflammation to potentially increase neuroinflammation is via gut dysbiosis. We hypothesized that a high fat diet would cause gut microbe dysbiosis, and subsequently: neuroinflammation and cognitive decline. Using 7-month old male Sprague Dawley rats, this study examined whether 8 weeks on a high fat diet could impact performance on the water radial arm maze, gut microbe diversity and abundance, and microgliosis. We found that a high fat diet altered gut microbe populations compared to a low fat, control diet. However, we did not observe any significant differences between dietary groups on maze performance (a measure of spatial working memory) or microgliosis. Our data reveal a significant change to the gut microbiome without subsequent effects to neuroinflammation (as measured by microglia characterization and counts in the cortex, hippocampus, and hypothalamus) or cognitive performance under the parameters of our study. However, future studies that explore duration of the diet, composition of the diet, age of animal model, and strain of animal model, must be explored.
| S-EPMC6541285 | biostudies-other
Project description:Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.
| S-EPMC8034849 | biostudies-literature