Influence of obesity on remodeling of lung tissue and organization of extracellular matrix after blunt thorax trauma.

BACKGROUND: Previously, it has been shown that obesity is a risk factor for recovery, regeneration, and tissue repair after blunt trauma and can affect the rate of muscle recovery and collagen deposition after trauma. To date, lung tissue regeneration and extracellular matrix regulation in obese mice after injury has not been investigated in detail yet. METHODS: This study uses an established blunt thorax trauma model to analyze morphological changes and alterations on gene and protein level in lean or obese (diet-induced obesity for 16 ± 1 week) male C57BL/6 J mice at various time-points after trauma induction (1 h, 6 h, 24 h, 72 h and 192 h). RESULTS: Morphological analysis after injury showed lung parenchyma damage at early time-points in both lean and obese mice. At later time-points a better regenerative capacity of lean mice was observed, since obese animals still exhibited alveoli collapse, wall thickness as well as remaining filled alveoli structures. Although lean mice showed significantly increased collagen and fibronectin gene levels, analysis of collagen deposition showed no difference based on colorimetric quantification of collagen and visual assessment of Sirius red staining. When investigating the organization of the ECM on gene level, a decreased response of obese mice after trauma regarding extracellular matrix composition and organization was detectable. Differences in the lung tissue between the diets regarding early responding MMPs (MMP8/9) and late responding MMPs (MMP2) could be observed on gene and protein level. Obese mice show differences in regulation of extracellular matrix components compared to normal weight mice, which results in a decreased total MMP activity in obese animals during the whole regeneration phase. Starting at 6 h post traumatic injury, lean mice show a 50% increase in total MMP activity compared to control animals, while MMP activity in obese mice drops to 50%. CONCLUSIONS: In conclusion, abnormal regulation of the levels of extracellular matrix genes in the lung may contribute to an aberrant regeneration after trauma induction with a delay of repair and pathological changes of the lung tissue in obese mice.

Consumption of a high-fat diet does not potentiate the deleterious effects on lipid and protein levels and body development in rats subjected to maternal protein restriction.

Maternal undernutrition may cause injuries in several organs of the offspring, as well as lead to diseases in adulthood. Obesity and/or the consumption of a high-fat diet may also induce metabolic and cardiorespiratory diseases. We hypothesized that the consumption of a post-weaning high-fat diet would potentiate the deleterious effects of maternal protein undernutrition. This study evaluated the effects of the association of a low-protein diet during gestation and lactation with a post-weaning high-fat diet on the biochemical and ventilatory parameters of rats. Male Wistar rats from mothers who received a low-protein (9% of protein) or normoprotein diet during pregnancy and lactation received a high-fat (32% of total kilocalories from lipids) or a normal fat diet after weaning. Mass gain and somatic growth of the offspring were monitored. Also examined were biochemical chemical parameters and respiratory frequency, tidal volume (volume of air displaced in each normal respiratory cycle when extra effort is not applied), and pulmonary ventilation. Offspring from undernourished mothers presented lower birth weight (P = .0225), which remained until the end of lactation (P < .01). The rats that consumed high-fat diet and had been submitted to maternal undernutrition presented higher tidal volume when compared to the ones that consumed control diet at the 21st day of life (P Ë‚ .05). At 30 and 90 days, no further ventilatory changes were observed. Our data show that the consumption of a high-fat diet post-weaning did not seem to potentiate the changes induced by maternal undernutrition.

Maternal high fat diet compromises survival and modulates lung development of offspring, and impairs lung function of dams (female mice).

BACKGROUND: Epidemiological studies have identified strong relationships between maternal obesity and offspring respiratory dysfunction; however, the causal direction is not known. We tested whether maternal obesity alters respiratory function of offspring in early life. METHODS: Female C57Bl/6 J mice were fed a high or low fat diet prior to and during two rounds of mating and resulting pregnancies with offspring lung function assessed at 2 weeks of age. The lung function of dams was measured at 33 weeks of age. RESULTS: A high fat diet caused significant weight gain prior to conception with dams exhibiting elevated fasting glucose, and glucose intolerance. The number of surviving litters was significantly less for dams fed a high fat diet, and surviving offspring weighed more, were longer and had larger lung volumes than those born to dams fed a low fat diet. The larger lung volumes significantly correlated in a linear fashion with body length. Pups born from the second pregnancy had reduced tissue elastance compared to pups born from the first pregnancy, regardless of the dam's diet. As there was reduced offspring survival born to dams fed a high fat diet, the statistical power of lung function measures of offspring was limited. There were signs of increased inflammation in the bronchoalveolar lavage fluid of dams (but not offspring) fed a high fat diet, with more tumour necrosis factor-α, interleukin(IL)-5, IL-33 and leptin detected. Dams that were fed a high fat diet and became pregnant twice had reduced fasting glucose immediately prior to the second mating, and lower levels of IL-33 and leptin in bronchoalveolar lavage fluid. CONCLUSIONS: While maternal high fat diet compromised litter survival, it also promoted somatic and lung growth (increased lung volume) in the offspring. Further studies are required to examine downstream effects of this enhanced lung volume on respiratory function in disease settings.

Randomized, open-label, comparative phase IV study on the bioavailability of Ciclosporin Pro (Teva) versus Sandimmun® Optoral (Novartis) under fasting versus fed conditions in patients with stable renal transplants.

BACKGROUND: The influence of pre- or postprandial administration on pharmacokinetics of cyclosporine is supposed to be less in gel-based formulations than in microemulsions. This study was designed to investigate the influence of a high-fat meal on the pharmacokinetic profile of the two cyclosporine containing formulations Ciclosporin Pro (gel-based emulsion) and Sandimmun®Optoral (microemulsion) in renal transplant recipients. METHODS: A randomized, open-label, repeated-measurement, comparative phase IV trial was conducted with two sequence groups for nutrition condition (fasting→fed, fed→fasting) and two treatment phases (Sandimmun® Optoral → Ciclosporin Pro), each covering both nutrition conditions. Primary pharmacokinetic variable of interest was the reduction of bioavailability due to high-fat food compared to fasting conditions measured by the difference D of ln-transformed bioavailability variables (AUCSS, τ, Css, max, und Css, min). RESULTS: A nutrition effect was found for both study medications with respect to the parameters AUCSS, τ and CSS, max, but not to CSS, min. The reduction of bioavailability caused by high-fat food was not significantly different for Sandimmun®Optoral and Ciclosporin Pro. CONCLUSIONS: An effect of high-fat breakfast prior to the morning dose on AUCSS, τ and CSS, max was found for Sandimmun® Optoral and for Ciclosporin Pro. Trough level monitoring did not capture ingestion-related variability. Conversion to Ciclosporin Pro seems to be safe with regard to intra-individual pharmacokinetic variability. TRIAL REGISTRATION: EudraCT No. 2009-011354-18 (29th April 2019).

High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease.

Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD.

Obesity impairs male fertility through long-term effects on spermatogenesis.

OBJECTIVE: This study aimed to investigate the effect and possible underlying mechanisms of high-fat diet-induced obesity on spermatogenesis in male rats. METHODS: A total of 45 male rats were randomly divided into control (n = 15, normal diet) and obesity groups (n = 30, high-fat diet) and were fed for 16 weeks. Body weight and organ indexes were determined after sacrifice. Indicators of reproductive function, including sperm count, sperm motility, apoptosis of spermatogenic cells, and oxidative stress levels, were measured. Serum metabolic parameters and reproductive hormones were also assayed. RESULTS: Compared with the control group, epididymal sperm motility in the obese rats was significantly decreased (P < 0.01). Morphological analysis of the obesity group showed vacuolar changes in seminiferous tubules, spermatogenic cell dysfunction, and increased apoptosis of spermatogenic cells in testicular tissue (P < 0.05). The calculated free testosterone (cFT) concentration in serum was decreased (P < 0.05), whereas the serum sex hormone-binding globulin (SHBG) level was significantly increased (P < 0.01). The superoxide dismutase (SOD) concentration decreased and the malondialdehyde (MDA) concentration increased in testis tissues; however, neither changes were statistically significant (P > 0.05). RESULTS: Nutritional obesity can damage spermatogenesis in male rats due to long-term effects on spermatogenesis.

Consumption of a High-Fat Diet Alters Perineuronal Nets in the Prefrontal Cortex.

A key factor in the development of obesity is the overconsumption of fatty foods, which, in addition to facilitating weight gain, alters neuronal structures within brain reward circuitry. Our previous work demonstrates that sustained consumption of a high-fat diet (HFD) attenuates spine density in the prefrontal cortex (PFC). Whether HFD promotes structural adaptation among inhibitory cells of the PFC is presently unknown. One structure of interest is the perineuronal net (PNN), a specialized extracellular matrix surrounding, primarily, parvalbumin-containing GABAergic interneurons. PNNs contribute to synaptic stabilization, protect against oxidative stress, regulate the ionic microenvironment within cells, and modulate regional excitatory output. To examine diet-induced changes in PNNs, we maintained rats on one of three dietary conditions for 21 days: ad libitum chow, ad libitum 60% high fat (HF-AL), or limited-access calorically matched high fat (HF-CM), which produced no significant change in weight gain or adiposity with respect to chow controls. The PNN "number" and intensity were then quantified in the prelimbic (PL-PFC), infralimbic (IL-PFC), and ventral orbitofrontal cortex (OFC) using Wisteria floribunda agglutinin (WFA). Our results demonstrated that fat exposure, independent of weight gain, induced a robust decrease in the PNN intensity in the PL-PFC and OFC and a decrease in the PNN number in the OFC.

What is new about diet in hepatic encephalopathy.

There is a relationship between hepatic encephalopathy (HE) protein malnutrition and muscle wasting. Muscle may play an alternative role in ammonia detoxification. Molecular mechanisms responsible for muscle depletion are under investigation. Specific nutrients may interact to reverse the molecular pathways involved in muscle wasting at an early stage. Training exercises have also been proposed to improve skeletal muscle mass. However, these data refer to small groups of patients. The amelioration of muscle mass may potentially help to prevent HE. The pathogenesis of HE is associated with modifications of the gut microbiota and diet is emerging to play a relevant role in the modulation of the gut milieu. Vegetarian and fibre-rich diets have been shown to induce beneficial changes on gut microbiota in healthy people, with reduction of Bacteroides spp., Enterobacteriaceae, and Clostridium cluster XIVa bacteria. By way of contrast, it has been suggested that a high-fat or protein diet may increase Firmicutes and reduce Bacteroidetes phylum. Milk-lysozyme and milk-oligosaccharides have also been proposed to induce a "healthy" microbiota. At present, no studies have been published describing the modification of the gut microbiota in cirrhotic patients with HE as a response to specific diets. New research is needed to evaluate the potentiality of foods in the modulation of gut microbiota in liver disease and HE.

Differential Effects of Pioglitazone in the Hippocampal CA1 Region Following Transient Forebrain Ischemia in Low- and High-Fat Diet-Fed Gerbils.

In the present study, we investigated the effects of pioglitazone (PGZ) in the hippocampal CA1 region of low- or high-fat diet (LFD or HFD) fed gerbils after transient forebrain ischemia. After 8 weeks of LFD or HFD feeding, PGZ (30 mg/kg) was intraperitoneally administered to the gerbils, following which ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. Administration of PGZ significantly reduced the ischemia-induced hyperactivity 1 day after ischemia/reperfusion in both LFD- and HFD-fed gerbils. At 4 days after ischemia/reperfusion, the neurons were significantly reduced and microglial activation was observed in the hippocampal CA1 region in LFD- and HFD-fed gerbils. The microglial activation was more prominent in the HFD-fed gerbils compared to the LFD-fed gerbils. Administration of PGZ ameliorated ischemia-induced neuronal death and microglial activation in the hippocampal CA1 region 4 days after ischemia/reperfusion in the LFD-fed gerbils, but not in the HFD-gerbils. At 6 h after ischemia/reperfusion, tumor necrosis factor-α (TNF-α) and interlukin-1ß (IL-1ß) levels were significantly increased in the hippocampal homogenates of LFD-fed group compared to control group, and HFD feeding further increased TNF-α and IL-1ß levels. PGZ treatment significantly ameliorated the increase of TNF-α and IL-1ß levels in LFD-fed gerbils, not in the HFD-fed gerbils. At 12 h after ischemia/reperfusion, superoxide dismutase (SOD) and malondialdehyde (MDA) levels in hippocampal homogenates were significantly increased in the LFD-fed group compared to the control group, and HFD feeding significantly showed relatively reduction in SOD activity and increase in MDA level. PGZ administration significantly reduced the increase in MDA levels 12 h after ischemia/reperfusion in the LFD-fed gerbils, but not in the HFD-fed gerbils. These results suggest that PGZ ameliorates the neuronal damage induced by ischemia by maintaining the TNF-α, IL-1ß, SOD and MDA levels in LFD-fed gerbils. In addition, HFD feeding affects the modulation of these parameters in the hippocampus after transient forebrain ischemia.

High-fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats.

Central application of apelin elevates blood pressure and influences neuroendocrine responses to stress and food consumption. However, it is not known whether the central cardiovascular effects of apelin depend also on caloric intake or chronic stress. The purpose of the present study was to determine the effects of intracerebroventricular administration of apelin on blood pressure (mean arterial blood pressure) and heart rate in conscious Sprague-Dawley rats consuming either a normal-fat diet (NFD) or high-fat diet (HFD) for 12 weeks. During the last 4 weeks of the food regime, the rats were exposed (NFDS and HFDS groups) or not exposed (NFDNS and HFDNS groups) to chronic stress. Each group was divided into two subgroups receiving intracerebroventricular infusions of either vehicle or apelin. Apelin elicited significant increase of mean arterial blood pressure and heart rate in the NFDNS rats. This effect was abolished in the HFDNS, HFDS and NFDS groups. HFD resulted in a significant elevation of blood concentrations of total cholesterol, triglycerides glucose and insulin. Chronic stress reduced plasma concentration of total and high-density lipoprotein cholesterol, and increased plasma corticosterone concentration and APJ receptor mRNA expression in the hypothalamus, whereas a combination of a HFD with chronic stress resulted in the elevation of plasma triglycerides, total cholesterol and low-density lipoprotein cholesterol, and in increased plasma corticosterone concentration, apelin concentration and APJ receptor mRNA expression in the hypothalamus. It is concluded that a HFD and chronic stress result in significant suppression of the central pressor action of apelin, and cause significant though not unidirectional changes of metabolic and endocrine parameters.

Trends in dietary fat and high-fat food intakes from 1991 to 2008 in the Framingham Heart Study participants.

Few longitudinal studies carried out in US adults have evaluated long-term dietary fat intakes and compared them with the national recommendations during the two-decade period when the prevalence of obesity and insulin resistance increased substantively. In the present study, we examined trends in the intakes of dietary fats and rich dietary sources of fats in the Framingham Heart Study Offspring Cohort over a 17-year period. The cohort was established in 1971-75 with follow-up examinations being conducted approximately every 4 years. Dietary data were collected using a semi-quantitative FFQ beginning in 1991 (exam 5). We included 2732 adults aged ≥ 25 years with complete dietary data in at least three examinations from 1991 to 2008. Descriptive statistics were generated using SAS version 9.3, and a repeated-measures model was used to examine trends in macronutrient and food intakes using R. Over the 17 years of follow-up, the percentage of energy derived from total fat and protein increased (27·3-29·8% of energy and 16·8-18·0% of energy, respectively) and that derived from carbohydrate decreased (51·0-46·8% of energy; P-trend < 0·001). Increases in the percentage of energy derived from all fat subtypes were observed, except for that derived from trans-fats, which decreased over time (P-trend < 0·001). Trends were similar between the sexes, although women exhibited a greater increase in the percentage of energy derived from saturated fat and less reduction in the percentage of energy derived from trans-fats (P interaction < 0·05). Trends in fat intake were similar across the BMI categories. The number of weekly servings of cheese, eggs, ice cream desserts, nuts, butter and sausages/processed meats increased, whereas the intake of milk, margarine, poultry, confectioneries, chips and breads decreased (P-trend < 0·001). In this cohort of predominantly Caucasian older adults, the percentage of energy derived from dietary fats increased over time, but it remained within the national recommendations of less than 35 % of total energy, on average.

Pharmacokinetics and Safety of Dapoxetine Hydrochloride in Healthy Chinese Men: Impact of Dose and High-Fat Meal.

Dapoxetine is the first oral medication specifically developed for the on-demand treatment of premature ejaculation. The pharmacokinetics and safety of 30 mg (n = 40) and 60 mg (n = 38) dapoxetine in healthy Chinese under fasted and fed states were assessed in 2 studies. Both studies are random, single-center, 2-period, open-label, 2-way crossover designs. Plasma concentration of dapoxetine was determined by high-performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated using noncompartmental analysis. Dapoxetine was quickly absorbed and reached maximum concentration 1 to 3 hours after oral administration. Elimination was biphasic, and the plasma concentration decreased to 3% to 7% of maximum concentration by 24 hours while half-life was 15 to 18 hours. Meantime, high-fat meals slightly increased its exposure. Both doses of dapoxetine were well tolerated. The adverse events in the high-dose group under fasted and fed states were 37.9% and 19.0%, respectively.

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts.

Background: Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Using chromatin immunoprecipitation sequencing, we previously demonstrated that late-gestation diabetes, maternal high fat (HF) diet, and the combination causes distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to maternal diabetes and maternal H diet. Methods: Microarray gene expression profiling of hearts from diabetes exposed, HF diet exposed, and combination exposed newborn rats was compared to controls. Functional annotation, pathway and network analysis of differentially expressed genes were performed in combination exposed and control newborn rat hearts. Further downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3ß, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results: Transcriptional analysis identified significant fuel-mediated changes in offspring cardiac gene expression. Specifically, functional pathways analysis identified two key signaling cascades that were functionally prioritized in combination exposed offspring hearts: (1) downregulation of fibroblast growth factor (FGF) activated PI3K/AKT pathway and (2) upregulation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α) mitochondrial biogenesis signaling. Functional metabolic and histochemical assays supported these transcriptome changes, corroborating diabetes- and diet-induced cardiac transcriptome remodeling and cardiac metabolism in offspring. Conclusion: This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on regulation of heart health.

Effects of physical activity and melatonin on brain-derived neurotrophic factor and cytokine expression in the cerebellum of high-fat diet-fed rats.

AIMS: Obesity suppresses brain-derived neurotrophic factor (BDNF) expression and increases the expression of pro-inflammatory cytokines. Herein, we assessed whether exercise training (ET), melatonin administration (MT), or their combination can affect the expressions of BDNF and cytokines in the cerebellum of high-fat diet (HFD)-fed rats. METHODS: Wistar rats (4 weeks old) were divided into five groups: normal diet (ND)-fed control (ND-SED), HFD-fed control (HFD-SED), HFD-fed ET (HFD-ET), HFD-fed MT (HFD-MT), and HFD-fed MT plus ET (HFD-ETMT) group. The rats were fed ND or HFD for 17 weeks. Rats were subjected to ET (running on a treadmill) and/or MT (melatonin 5 mg/kg body weight, i.p.) for 9 weeks, 8 weeks after beginning the diet intervention. Changes in BDNF and cytokine expression levels were determined using immunoblotting and cytokine arrays, respectively, 36 hours following the last bout of ET. RESULTS: Neither HFD-ET nor HFD-MT rats exhibited enhanced BDNF expression in the cerebellum, but HFD-ETMT rats had higher level of BDNF expression compared with the others. The expression of TrkB, a BDNF receptor, was higher in HFD-ETMT rats than in HFD-ET and HFD-MT rats. HFD enhanced the expression of interleukin (IL)-1, IL-2, and interferon-γ but reduced the expression of IL-4, IL-6, and IL13. ET and ET plus MT counteracted these HFD-induced changes in cytokine expressions. CONCLUSION: Exercise in combination with melatonin confers the potential benefits of increasing BDNF and improving HFD-induced dysregulations of cytokines in the cerebellum.

Maternal high-fat diet stimulates proinflammatory pathway and increases the expression of Tryptophan Hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF) in adolescent mice hippocampus.

Maternal high-fat diet (HFD) consumption can promote a systemic inflammatory condition that may impair the offspring brain development, damaging memory and learning, when it reaches the hippocampus. This study aims to evaluate maternal HFD effects, during pregnancy and lactation, upon dams/mice offspring nutritional status, protein and gene expression of inflammatory pathway (JNK, pJNK and TNF-α), serotonin system molecules (Tryptophan Hydroxylase 2 (TPH2), key-enzyme of serotonin synthesis, serotonin transporter (SERT); 5-HT1A serotonergic receptor (5-HT1A)) and brain derived neurotrophic factor (BDNF) on recently weaned mice offspring hippocampus. Female Swiss mice were fed a control diet (CD, 11,5% fat) or a HFD (45.0% fat) from pre-mating to lactation. After weaning, the offspring received CD up to 28 post-natal days (PND28). Body weight and visceral adiposity (retroperitoneal and gonadal adipose tissue) of dams and offspring were measured. After euthanasia, the offspring hippocampus was dissected for evaluations of BDNF, inflammatory pathway and serotonergic system molecules protein and gene expression, through the techniques of Western Blotting, RTqPCR and ELISA. Our findings show that, during pregnancy, HFD-dams and HFD-offspring exhibited an increase in body weight gain and visceral adipose tissue compared to control animals. The hippocampus of HFD-offspring showed increased protein expression of TPH2, BDNF, pJNK and increased mRNA levels of TNF-α. However, the TPH2 increase in HFD-offspring did not alter hippocampal serotonin levels quantified through ELISA. Maternal HFD promoted an obesity phenotype in its offspring with increased body weight and visceral adiposity, increased protein and gene expression of the pro-inflammatory proteins pJNK and TNF-α. These changes were accompanied by increased TPH2 and BDNF protein expression. Thus, our findings show that maternal HFD during gestation and lactation increased pJNK and TNF-α expression in their offspring hippocampus indicating a pro-inflammatory state, with increased BDNF expression and alterations in its serotonergic system reflected by increased TPH2 expression.

A study on molecular mechanisms of adiposis induced by long-term treatment of high-fat and high-sucrose in C57BL/6J mice.

Adiposis is reputed as a twin disease of type 2 diabetes and greatly harmful to human health. In order to understand the molecular mechanisms of adiposis, the changes of physiological, pathological, epigenetic and correlative gene expression were investigated during the adiposis development of C57BL/6J mice induced by long time (9 months) high-fat and high-sucrose diet (HFSD) sustainably. The results showed that mRNA transcription level of the Leptin, Glut4 and Glut2 genes have been obviously changed, which exhibit a negative correlation with methylation on their promoter DNA. The results also revealed that HFSD induced higher level of DNA methyltransferase 1 (DNMT1) in fat tissue might play important role in regulating the changes of methylation pattern on Glut4 and Leptin genes, and which might be one of the molecular mechanisms for the adiposis development.

Hydroxytyrosol supplementation ameliorates the metabolic disturbances in white adipose tissue from mice fed a high-fat diet through recovery of transcription factors Nrf2, SREBP-1c, PPAR-γ and NF-κB.

BACKGROUND: White adipose tissue (WAT) have a relevant metabolic and inflammatory function, in overweight or obesity conditions. In this regard, the WAT under over feeding nutrition present a significant increment in oxidative stress, pro-inflammatory status and depletion of n-3 long chain polyunsaturated fatty acid. Hydroxytyrosol (HT) is a polyphenol with important cytoprotective effects, and this molecule can modulate the gene expression, transcription factors and enzymatic activity. OBJECTIVE: Therefore, the purpose of this study was evaluate the anti-inflammatory, anti-oxidant and anti-lipogenic effects of HT supplementation mice and the molecular adaptations involved, on dysfunctional WAT from high-fat diet (HFD)-fed mice. METHODS AND RESULTS: Male C57BL/6 J mice received (i) control diet (10% fat); (ii) control diet + HT (daily doses of 5 mg kg body weight), (iii) HFD (60% fat); or (iv) HFD + HT for 12 weeks. HFD-fed mice exhibited: (i) WAT hypertrophy; (ii) oxidative stress and depletion of antioxidant defenses, (iii) increased lipogenesis and pro-inflammatory status, (iv) depletion of n-3 LCPUFA and (v) up-regulation of NF-κB and SREBP 1c with down-regulation Nrf2, and PPAR-γ. HT supplementation attenuated the metabolic impairment produced by HFD in WAT, attenuating increment of NF-κB and SREBP 1c, and increasing the activity of Nrf2 and PPAR-γ. CONCLUSION: Supplementation with HT improve the WAT dysfunction induced by HDF in mice through the modulation of transcription factors NF-κB, Nrf2, SREBP-1c and PPAR-γ as well as their target genes, involved in inflammation, antioxidant defenses and lipogenesis.

Allium tuberosum alleviates diabetic nephropathy by supressing hyperglycemia-induced oxidative stress and inflammation in high fat diet/streptozotocin treated rats.

The objective of this study was to evaluate the effect of the butanol fraction from Allium tuberosum (BFAT) in high fat diet/streptozotocin (HFD/STZ) induced diabetic nephropathy. Wistar rats were fed with HFD for 4 weeks and thereafter administered with 35 mg/kg STZ intraperitoneally. Diabetic rats were treated with BFAT (100 or 400 mg/kg) and metformin (150 mg/kg) for 40 days. After treatment, the blood, urine and kidney tissues were obtained for biochemical and histological analysis. BFAT markedly decreased blood glucose, serum creatinine, blood urea nitrogen and urinary albumin levels in diabetic rats. Furthermore, BFAT upregulated renal antioxidant enzymes status (glutathione, superoxide dismutase and catalase) and decreased lipid peroxidation product in diabetic rats as well as reduced the levels of renal pro-inflammatory cytokines in diabetic rats. In addition, BFAT significantly decreased serum and renal levels of triglyceride and cholesterol in the treated diabetic rats. These results revealed that A. tuberosum possesses attenuative effects against diabetic nephropathy.

High-fat diet-induced hyperglutamatergic activation of the hippocampus in mice: A proton magnetic resonance spectroscopy study at 9.4T.

The aim of this study was to investigate the long-term neurochemical alterations in the hippocampus of mice fed a high-fat diet (HFD) while plasma leptin and corticosterone levels were monitored. Although metabolic disturbances induced by the excess intake of fat are assumed to cause depression, the relationship underlying dysfunctional adipose tissue, stress hormone release, and excitatory metabolism has not been fully understood yet. Four-week-old male C57BL/6 mice were separated into a HFD-fed group (n = 8) and low-fat diet-fed group (n = 8). Proton magnetic resonance spectroscopy was used to measure the long-term changes in neurochemicals in the hippocampus at 0, 5, and 10 weeks and blood samples were taken at the same time to assess plasma hormones levels. At the end of the experiment, magnetic resonance imaging was performed to quantify abdominal fat accumulation. At 10 weeks, corticosterone and leptin levels were significantly increased in the HFD group compared with the low-fat diet group. In addition, aspartate, glutamate, total choline, and N-acetylaspartic acid levels were significantly increased, but glutamine/glutamate ratios were substantially decreased at 10 weeks in the HFD group. These results were compatible with HFD-induced acute stress responses and changes in N-methyl-d-aspartate receptor-induced plasticity. These findings demonstrated that the long-term ingestion of a HFD induced hyperglutamatergic metabolism and altered glutamine-glutamate cycling. Therfore, it is suggested that hypothalamic-pituitary-adrenal dysfunction and hyperglutamatergic activation in the hippocampus resulting from the HFD.

Re-establishing normal diet following high fat-diet-induced obesity reverses the altered salivary composition in Wistar rats.

Background Obesity has been implicated in impaired salivary secretion. This study aimed at evaluating the influence of diet-induced obesity on salivary secretion and how re-feeding with normal diet would affect changes in salivary secretion associated with diet-induced obesity. Methods Weaning rats weighing 55-65 g were randomly divided into three groups (control, diet-induced obese, re-fed obese) of seven rats each. The diet-induced obese group was fed a high-fat diet for 15 weeks, whereas the re-fed obese group received normal diet for another 15 weeks following the 15 weeks of high-fat diet. After treatment, blood and stimulated saliva samples were collected for the analyses of total protein, electrolytes, amylase, Immunoglobulin A (IgA), leptin and ghrelin. Tissue total protein, nitric oxide level, expressions of Na+/K+-ATPase, muscarinic (M3) receptor and aquaporin 5 in the submandibular glands were determined. Data were presented as mean±SEM and compared using independent student t-test and ANOVA with Tukey's post-hoc test. Results Results indicated increases in the levels of salivary calcium, phosphate, bicarbonate and leptin, whereas the levels of salivary amylase and ghrelin showed reduction in the obese group compared with the control. Most of these changes were reversed in the re-fed obese group. There were no significant differences in salivary lag time, flow rate, levels of tissue total protein, nitric oxide and the relative expressions of M3 receptor, Na++/K+-ATPase and aquaporin 5 in the submandibular glands between the obese and control groups. Conclusions Diet-induced obesity lead to some changes in salivary factors which were reversed by returning to normal diet.