High-carbohydrate High-fat Research Articles

Effects of Gossypetin on Glucose Homeostasis in Diet-Induced Pre-Diabetic Rats.

Natural flavonoids exert many potential health benefits, including anti-hyperglycaemic effects. However, the effects of gossypetin (GTIN) on glucose homeostasis in pre-diabetes have not yet been investigated. This study examined the effects of GTIN on key markers of glucose homeostasis in a diet-induced pre-diabetic rat model. Pre-diabetes was induced by allowing the animals to feed on a high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose water for 20 weeks. Following pre-diabetes induction, the pre-diabetic animals were sub-divided into five groups (n = 6), where they were either orally treated with GTIN (15 mg/kg) or metformin (MET) (500 mg/kg), both with and without dietary intervention, over a 12-week period. The results demonstrated that animals in the untreated pre-diabetic (PD) control group exhibited significantly higher fasting and postprandial blood glucose levels, as well as elevated plasma insulin concentrations and increased homeostatic model assessment for insulin resistance (HOMA2-IR) index, relative to the non-pre-diabetic (NPD) group. Similarly, increased caloric intake, body weight and plasma ghrelin levels were observed in the PD control group. Notably, these parameters were significantly reduced in the PD animals receiving GTIN treatment. Additionally, glycogen levels in the liver and skeletal muscle, which were disturbed in the PD control group, showed significant improvement in both GTIN-treated groups. These findings may suggest that GTIN administration, with or without dietary modifications, may offer therapeutic benefits in ameliorating glucose homeostasis disturbances associated with the PD state.

Organosulfur Compounds, S-Allyl-L-Cysteine and S-Ethyl-L-Cysteine, Target PCSK-9/LDL-R-Axis to Ameliorate Cardiovascular, Hepatic, and Metabolic Changes in High Carbohydrate and High Fat Diet-Induced Metabolic Syndrome in Rats.

Metabolic syndrome (MetS) is an ever-evolving set of diseases that poses a serious health risk in many countries worldwide. Existing evidence illustrates that individuals with MetS have a 30%-40% higher chance of acquiring type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or both. This study was undertaken to uncover the regulatory role of natural organosulfur compounds (OSCs), S-allyl-L-cysteine (SAC), and S-ethyl-L-cysteine (SEC), in targeting high carbohydrate high fat (HCHF)-diet-induced MetS-associated risk management. Our findings suggested that SAC and SEC ameliorated HCHF-diet-induced diabetic profiles, plasma lipid and lipoprotein level, liver function, oxidative-stress, inflammatory cytokines, and chemokines including monocyte chemoattractant protein-1 (MCP-1), lipid peroxidation, plasma proprotein convertase subtilisin/kexin type-9 (PCSK-9), and high-sensitivity C-reactive protein (hs-CRP). Moreover, the assessment of the hepatic mRNA expression of the key genes involved in cholesterol homeostasis depicted that SAC and SEC downregulated the PCSK-9 mRNA expression via targeting the expression of HNF-1α, a transcriptional activator of PCSK-9. On the other hand, the LDL-receptor (LDL-R) expression was upregulated through the activation of its transcriptional regulator sterol regulatory element binding protein-2 (SREBP-2). In addition, the activity and the mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme-A reductases (HMG-R) and peroxisome proliferator-activated receptors (PPARs) were also improved by the treatment of SAC and SEC. We concluded that SAC and SEC can protect against MetS via improving the lipid and lipoprotein content, glycemic indices, hepatic function, targeting the inflammatory cascades, and oxidative imbalance, regulation of the mRNA expression of PCSK-9, LDL-R, SREBP-2, HNF-1α, PPARs, and inflammatory biomarkers.

Erythropoietin hyporesponsiveness in non-alcoholic fatty liver disease.

Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness. To test our hypothesis, we evaluated the effect of EPO in healthy rats and rats with NAFLD induced by a high-fat, high-carbohydrate (HFHC) diet. After 12 weeks on the HFHC diet, NAFLD rats showed lower erythroid response to EPO treatment than healthy rats. We, then, determined that the primary cause of EPO hyporesponsiveness could be iron deficiency associated with inflammation, which reduces erythroid cell production. Specifically, the concentrations of hepcidin, ferritin, transferrin and white blood cells in NAFLD rats were 12.8-, 16.4-, 2.51- and 1.40-fold higher than those in healthy rats, respectively. However, erythroid cell types in the bone marrow of NAFLD rats were significantly reduced. In conclusion, our data suggest that NAFLD could be a risk factor for EPO responsiveness, which is attributed to functional iron deficiency associated with inflammation.

ROLE OF H2S AS A PREDICTOR OF CARDIOVASCULAR DISEASE IN METABOLIC SYNDROME

Objective: One of the possible protective factors that can protect target vascular cells (endothelial, smooth muscle cells) from damage during the development of metabolic syndrome (MetS) is hydrogen sulfide (H2S). Design and method: A study was carried out in male Wistar rats weighing 250–320 g, 140 days old at the end of research. The rats from the control group were fed standard rat chow. The rats from the experimental group had a high-fat high-carbohydrate (HFHC) diet. Biochemical parameters of rat blood were determined. The concentration of H2S in the blood serum and adipose tissue of rats was determined by the photometric method at 670 nm. The expression of the H2S synthesis enzyme CSE was studied in aortic tissue samples using Western blot. Results: It was found that HFHC diet led to an increase in body weight, obesity, hyperglycemia, insulin resistance, dyslipidemia, and leptinemia in the experimental group rats. It was found that the concentration of H2S significantly decreased in the blood serum and adipose tissue of rats with MetS. The rate of production of H2S in adipose tissue of rats with MetS also decreased. In the aortic tissue of rats with MetS, there was a decrease in the amount of protein of the CSE. Conclusions: Changes in the activity of the H2S/CSE system in MetS may be additional evidence of the development of vascular dysfunction in metabolic disorders.

Ablation of histone methyltransferase Suv39h2 in hepatocytes attenuates NASH in mice

AimsNon-alcoholic steatohepatitis (NASH) is characterized by aberrant lipid metabolism in hepatocytes. We investigated the involvement of a histone H3K9 methyltransferase Suv39h2 in the pathogenesis of NASH. Methods and materialsNASH is induced by feeding the mice with a high-fat high-carbohydrate (HFHC) diet or a high-fat choline-deficient amino acid defined (HFD-CDAA) diet. The Suv39h2f/f mice were crossbred with the Alb-Cre mice to specifically delete Suv39h2 in hepatocytes. Key findingsAblation of Suv39h2 in hepatocytes improved insulin sensitivity of the mice fed either the HFHC diet or the CDAA-HFD diet. Importantly, Suv39h2 deletion significantly ameliorated NAFLD as evidenced by reduced lipid accumulation, inflammation, and fibrosis in the liver. RNA-seq uncovered Vanin-1 (Vnn1) as a novel transcriptional target for Suv39h2. Mechanistically, Suv39h2 repressed Vnn1 transcription in hepatocytes exposed to free fatty acids. Consistently, Vanin-1 knockdown normalized lipid accumulation in Suv39h2-null hepatocytes. Importantly, a significant correlation between Suv39h2, Vanin-1, and hepatic triglyceride levels was identified in NASH patients. SignificanceOur study uncovers a novel mechanism whereby Suv39h2 may contribute to NASH pathogenesis and suggests that targeting the Suv39h2-Vanin-1 axis may yield novel therapeutic solutions against NASH.

Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats

Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimer’s disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially affected. Our results offer a possible mechanistic explanation for the obesity paradox.

Vitamin D3 mitigates type 2 diabetes induced by a high carbohydrate-high fat diet in rats: Role of the purinergic system

This study evaluated the effect of vitamin D3 (VIT D3) supplementation on the enzymatic activities and density of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), ecto-5-nucleotidase (E-5′-NT), adenosine deaminase (ADA), as well as the density of P2 × 7R, P2Y12R, A1R, A2AR receptors, IL-1β, and oxidative parameters in type 2 diabetic rats. Forty male Wistar rats were fed a high carbohydrate-high fat diet (HCHFD) and received an intraperitoneal injection containing a single dose of streptozotocin (STZ, 35 mg/kg). Animals were divided into four groups: 1) control; 2) control/VIT D3 12 µg/kg; 3) diabetic; and 4) diabetic/VIT D3 12 µg/kg. Results show that VIT D3 reduced blood glucose, ATP hydrolysis, ADA activity, P2Y12R density (platelets), as well as ATP, ADP, and AMP hydrolysis and ADA activity (synaptosomes). Moreover, VIT D3 increased insulin levels and AMP hydrolysis (platelets) and improved antioxidant defense. Therefore, we suggest that VIT D3 treatment modulates hyperglycemia-induced changes via purinergic enzymes and receptor expression, consequently attenuating insulin homeostasis dysregulation in the diabetic state.

Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice

Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tissue is associated with obesity and atherosclerosis in LDLR−/− mice fed a high fat-high carbohydrate. The present study was undertaken to determine whether inhibition of 5-lipoxygenase activating protein is efficacious in attenuating adipose tissue inflammation in LDLR−/− mice fed a high fat-high carbohydrate. 10-week old male LDLR−/− mice were fed a high fat-high carbohydrate diet for 22-weeks, with or without MK886 (40 mg/kg/day, ad libitum) a well-established 5-lipoxygenase activating protein inhibitor. All mice had an approximate 2-fold increase in total body weight, but a 6-week course of MK886 treatment had differential effects on adipose tissue size, without affecting macrophage accumulation. MK886 exacerbated the dyslipidemia, increased serum amyloid A content of high-density lipoproteins and caused a profound hepatomegaly. Dyslipidemia and increased serum amyloid A were concomitant with increases in atherosclerosis. In conclusion, MK886 paradoxically exacerbated hyperlipidemia and the pro-inflammatory phenotype in a mouse model of diet-induced atherosclerosis, possibly via a disruption of hepatic lipid metabolism and increased inflammation.

Momordica balsamina improves glucose handling in a diet-induced prediabetic rat model

Prolonged exposure to high energy diets has been implicated in the development of pre-diabetes, a long-lasting condition that precedes type 2 diabetes mellitus (T2DM). A combination of pharmacological treatment and dietary interventions are recommended to prevent the progression of pre-diabetes to T2DM. However, poor patient compliance leads to negligence of the dietary intervention and thus reduced drug efficiency. Momordica balsamina (MB) has been reported to possess anti-diabetic effects in type 1 diabetic rats. However, the effects of this medicinal plant in conjunction with dietary intervention on pre-diabetes have not yet been established. Consequently, this study sought to evaluate the effects of MB on glucose homeostasis in a diet-induced pre-diabetes rat model in the presence and absence of dietary intervention. Pre-diabetes was induced on male Sprague Dawley rats by a high fat high carbohydrate (HFHC) diet for a period of 20 weeks. Pre-diabetic male Sprague Dawley rats were treated with MB (250 mg/kg p.o.) in both the presence and absence of dietary intervention once a day every third day for a period of 12 weeks. The administration of MB with and without dietary intervention resulted in significantly improved glucose homeostasis through reduced caloric intake, body weights, with reduced plasma ghrelin concentration and glycated hemoglobin by comparison to the pre-diabetic control. MB administration also improved insulin sensitivity as evidenced by the expression of glucose transporter 4 (GLUT 4) and glycogen synthase on the prediabetic treated animals. These results suggest that MB has the potential to be used to manage pre-diabetes and prevent the progression to overt type 2 diabetes as it demonstrated the ability to restore glucose homeostasis even in the absence of dietary and lifestyle intervention.

Cholesterol Exacerbates the Pathophysiology of Non-Alcoholic Steatohepatitis by Upregulating Hypoxia-Inducible Factor 1 and Modulating Microcirculatory Dysfunction.

Cholesterol is a pivotal lipotoxic molecule that contributes to the progression of Non-Alcoholic Steatohepatitis NASH). Additionally, microcirculatory changes are critical components of Non-Alcoholic Fatty Liver Disease (NAFLD) pathogenesis. This study aimed to investigate the role of cholesterol as an insult that modulates microcirculatory damage in NAFLD and the underlying mechanisms. The experimental model was established in male C57BL/6 mice fed a high-fat high-carbohydrate (HFHC) diet for 39 weeks. Between weeks 31-39, 2% cholesterol was added to the HFHC diet in a subgroup of mice. Leukocyte recruitment and hepatic stellate cells (HSC) activation in microcirculation were assessed using intravital microscopy. The hepatic microvascular blood flow (HMBF) was measured using laser speckle flowmetry. High cholesterol levels exacerbated hepatomegaly, hepatic steatosis, inflammation, fibrosis, and leukocyte recruitment compared to the HFHC group. In addition, cholesterol decreased the HMBF-cholesterol-induced activation of HSC and increased HIF1A expression in the liver. Furthermore, cholesterol promoted a pro-inflammatory cytokine profile with a Th1-type immune response (IFN-γ/IL-4). These findings suggest cholesterol exacerbates NAFLD progression through microcirculatory dysfunction and HIF1A upregulation through hypoxia and inflammation. This study highlights the importance of cholesterol-induced lipotoxicity, which causes microcirculatory dysfunction associated with NAFLD pathology, thus reinforcing the potential of lipotoxicity and microcirculation as therapeutic targets for NAFLD.

Investigating the Association Between Diet-Induced "Leaky Gut" and the Development of Prediabetes.

Chronic consumption of a high-calorie diet compromises the gut microbiota and the integrity of the intestinal wall, which causes translocation of bacterial lipopolysaccharides (LPS) into the blood. This elicits the secretion of pro-inflammatory cytokines, resulting in inflammation. However, how a high-fat high carbohydrate diet affects intestinal permeability and its possible role in the development of prediabetes have not been investigated. This study investigated the effects of HFHC diet-induced prediabetes on gut microbiota and intestinal permeability in male Sprague Dawley rats. The animals were randomly assigned into the non-prediabetic (NPD) and diet-induced prediabetic (PD) groups (n=6) for 20 weeks. Then, the fecal samples were analyzed to measure the gut microbiota level of Firmicutes, Bacteroidetes, and Proteobacteria in both animal groups. Blood glucose, plasma insulin, serum zonulin, plasma LPS, soluble CD14, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and intestinal fatty-acid binding protein (IFABP) concentrations were measured. The PD group had a reduction in the Firmicutes and an increase in Bacteroidetes and Proteobacteria levels compared to those in the NPD group. Blood glucose, insulin concentration, serum zonulin, and plasma sCD14 concentrations in the PD group increased significantly, while plasma LPS concentrations were similar to the NPD group. Concentrations of plasma TNF-α, IL-6, CRP, and IFABP, an intracellular protein expressed in the intestine, increased in PD compared to the NPD group. the study results cumulatively suggest that chronic consumption of the HFHC diet may be associated with the dysregulation of gut microbiota, leading to increased intestinal permeability.

High-fat, high-carbohydrate diet-induced prediabetes preconception in Sprague-Dawley rats as a risk factor for the development of preeclampsia: assessing changes in placental metabolic insults.

Hyperglycemia preconception deranges the establishment of a functional placenta; however, the risk of developing preeclampsia (PE) in prediabetic patients remains obscure. The aim was to assess abnormal placental changes as a risk factor for the development of PE in high-fat, high-carbohydrate (HFHC) diet-induced prediabetic (PD) rats. HFHC diet-induced female prediabetic Sprague-Dawley rats were mated, and blood glucose concentrations, mean arterial pressure (MAP), and body weights were monitored on gestational days (GNDs) 0, 9, and 18. On GND 18, animals were euthanized. Blood and placentas were collected for biochemical analysis. Prediabetic rats showed significantly increased blood glucose concentration, proinflammatory cytokines, MAP, placental weight, and fetoplacental ratio compared with non-prediabetic (NPD) rats. Prediabetic rats showed significantly decreased placental vascular endothelial growth factor receptor 1 (VEGFR1) and placental growth factor (PLGF) and plasma nitric oxide (NO) compared with NPD. Prediabetes may have promoted endothelial dysfunction in the placenta and hypoxia, thus reducing PLGF and VEGFR1, which may have promoted proinflammation, endothelial dysfunction associated with NO decline, and hypertension, which is also observed in preeclamptic patients. Prediabetes may have promoted lipogenesis in placentas and fetuses that may have induced macrosomia and IUGR, also observed in preeclamptic patients. The findings from this study highlight the need for screening and monitoring of prediabetes during pregnancy to reduce the risk of developing preeclampsia.

Assessment of melatonin's therapeutic effectiveness against hepatic steatosis induced by a high-carbohydrate high-fat diet in rats.

Several studies have demonstrated the protective effects of melatonin against metabolic diseases, such as liver steatosis. However, its therapeutic effects have received less scrutiny. The present study aimed to explore melatonin's therapeutic effectiveness in treating non-alcoholic fatty liver disease (NAFLD) induced by a high-carbohydrate high-fat (HCHF) diet in rats. The NAFLD was developed in male Wistar rats using an HCHF diet for 8 weeks. Afterward, they were given melatonin orally for four weeks at doses of 5 mg/kg, 10 mg/kg, and 30 mg/kg, along with the HCHF diet. In addition, six age-matched healthy rats received the highest dose of melatonin (30 mg/kg) for the same duration. Rats on the HCHF diet exhibited obesity, dyslipidemia, hyperglycemia, glucose intolerance, insulin resistance, inflammation, oxidative stress, and liver injury (steatosis). Melatonin treatment at 10 mg/kg and 30 mg/kg reduced body weight, adiposity index, oxidative damage, and inflammation but did not affect impaired glucose metabolism induced by the HCHF diet. Meanwhile, the highest dose of melatonin (30 mg/kg) reduced the liver steatosis index in HCHF rats but caused mild liver damage in healthy rats. In conclusion, using melatonin demonstrated positive outcomes in treating NAFLD induced by the HCHF diet in rats, with no noteworthy effects observed in healthy rats. A moderate dosage of 10 mg/kg of melatonin proved to be a safer and more efficient method for reducing HCHF diet-induced NAFLD in rats. Higher melatonin doses should be cautiously administered due to potential disruptions in lipid metabolism and the risk of liver complications.

The Mechanism of Kelulut Honey in Reversing Metabolic Changes in Rats Fed with High-Carbohydrate High-Fat Diet.

Metabolic syndrome (MetS) is composed of central obesity, hyperglycemia, dyslipidemia and hypertension that increase an individual's tendency to develop type 2 diabetes mellitus and cardiovascular diseases. Kelulut honey (KH) produced by stingless bee species has a rich phenolic profile. Recent studies have demonstrated that KH could suppress components of MetS, but its mechanisms of action are unknown. A total of 18 male Wistar rats were randomly divided into control rats (C group) (n = 6), MetS rats fed with a high carbohydrate high fat (HCHF) diet (HCHF group) (n = 6), and MetS rats fed with HCHF diet and treated with KH (HCHF + KH group) (n = 6). The HCHF + KH group received 1.0 g/kg/day KH via oral gavage from week 9 to 16 after HCHF diet initiation. Compared to the C group, the MetS group experienced a significant increase in body weight, body mass index, systolic (SBP) and diastolic blood pressure (DBP), serum triglyceride (TG) and leptin, as well as the area and perimeter of adipocyte cells at the end of the study. The MetS group also experienced a significant decrease in serum HDL levels versus the C group. KH supplementation reversed the changes in serum TG, HDL, leptin, adiponectin and corticosterone levels, SBP, DBP, as well as adipose tissue 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) level, area and perimeter at the end of the study. In addition, histological observations also showed that KH administration reduced fat deposition within hepatocytes, and prevented deterioration of pancreatic islet and renal glomerulus. In conclusion, KH is effective in preventing MetS by suppressing leptin, corticosterone and 11βHSD1 levels while elevating adiponectin levels.

Tilianin Protects against Nonalcoholic Fatty Liver Disease in Early Obesity Mice.

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most frequent types of liver disease in pediatric populations with obesity. Tilianin has multiple biological activities including anti-inflammatory and antioxidant. Here, we aim to explore the functions and possible mechanisms of tilianin on NAFLD in obese children. A high-fat high-carbohydrate (HFHC) diet was used to feed 21-d-old mice. Tilianin was administered at a dose of 10 or 20 mg/kg daily. HFHC-fed mice gained weight, increased liver index. The liver showed hepatocyte ballooning, inflammatory infiltration, and steatosis. Elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) and reduced the high-density lipoprotein cholesterol (HDL-C) level were found in HFHC-fed mice. Administration of tilianin significantly reduced these impairments. We further evaluated proteins related to lipid metabolism and observed that LXRα, SREBP-1c, FAS and ACC1 expression were blunted following tilianin administration. In addition, tilianin suppressed reactive oxygen species (ROS) overproduction and lipid peroxide 4-Hydroxynonenal expression, ascribed to its oxidative stress-modulating capacity. Tilianin also reversed the increase in F4/80 expression and proinflammatory cytokine levels. Of note, tilianin administration resulted in decreased protein levels of active caspase-1 and NOD-like receptor protein 3 (NLRP3) in HFHC-fed mice. Our study suggests that tilianin may ameliorate NAFLD in early obese mice by modulating lipids metabolism, oxidative stress, and inflammation, which may in part involve inhibiting NLRP3 inflammasome activation.

Exercise training attenuates pulmonary inflammation and mitochondrial dysfunction in a mouse model of high-fat high-carbohydrate-induced NAFLD

BackgroundNon-alcoholic fatty liver disease (NAFLD) can lead to pulmonary dysfunction that is associated with pulmonary inflammation. Moreover, little is known regarding the therapeutic role of exercise training on pulmonary pathophysiology in NAFLD. The present study aimed to investigate the effect of exercise training on high-fat high-carbohydrate (HFHC)-induced pulmonary dysfunction in C57BL/6 mice.MethodsMale C57BL/6 mice (N = 40) were fed a standard Chow (n = 20) or an HFHC (n = 20) diet for 15 weeks. After 8 weeks of dietary treatment, they were further assigned to 4 subgroups for the remaining 7 weeks: Chow (n = 10), Chow plus exercise (Chow+EX, n = 10), HFHC (n = 10), or HFHC plus exercise (HFHC+EX, n = 10). Both Chow+EX and HFHC+EX mice were subjected to treadmill running.ResultsChronic exposure to the HFHC diet resulted in obesity with hepatic steatosis, impaired glucose tolerance, and elevated liver enzymes. The HFHC significantly increased fibrotic area (p < 0.001), increased the mRNA expression of TNF-α (4.1-fold, p < 0.001), IL-1β (5.0-fold, p < 0.001), col1a1 (8.1-fold, p < 0.001), and Timp1 (6.0-fold, p < 0.001) in the lung tissue. In addition, the HFHC significantly altered mitochondrial function (p < 0.05) along with decreased Mfn1 protein levels (1.8-fold, p < 0.01) and increased Fis1 protein levels (1.9-fold, p < 0.001). However, aerobic exercise training significantly attenuated these pathophysiologies in the lungs in terms of ameliorating inflammatory and fibrogenic effects by enhancing mitochondrial function in lung tissue (p < 0.001).ConclusionsThe current findings suggest that exercise training has a beneficial effect against pulmonary abnormalities in HFHC-induced NAFLD through improved mitochondrial function.

Effects of tocotrienol on osteocyte-mediated phosphate metabolism in high-carbohydrate high-fat diet-induced osteoporotic rats

• Osteocytes act as mechanosensory cells to control bone remodelling. • Lower osteocyte numbers and higher empty lacunae are detected in bone loss. • Lower DMP1 and PHEX levels are detected in bone loss. • Longer treatment period is required to observe the changes in phosphate level. The potential of osteocyte-mediated phosphate homeostasis as a molecular link between metabolic syndrome and osteoporosis remains to be elucidated. This study investigated the osteocyte lacunar network, levels of osteocyte-specific molecules and phosphate in high-carbohydrate high-fat (HCHF) diet-fed osteoporotic rats with/without treatment of tocotrienol. The HCHF-fed rats had higher empty lacunae numbers, lower osteocyte numbers, dentin matrix acidic phosphoprotein 1 (DMP1), and phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) levels than the normal rats. Treatment with 100 mg/kg annatto tocotrienol significantly reduced empty lacunae numbers in the HCHF-fed rats. No changes in osteocyte number, DMP1, and PHEX levels between the tocotrienol-treated and vehicle-treated HCHF rats. Bone and serum phosphate levels were similar across all the groups. In conclusion, there are reductions in osteocyte numbers and expression of osteocyte-specific molecules in the HCHF diet-induced osteoporotic rats, but these changes are not reversed by the treatment with tocotrienol.

COMPARISON OF DIET INDUCED METABOLIC SYNDROME WITH ARTIFICIALLY INDUCED METABOLIC SYNDROME IN A RAT MODEL

Background: Metabolic syndrome is an emerging health problem. The diets rich in fats and refined carbohydrates and monosodium glutamate are considered major risk factors for this emerging epidemic. The aim of this study was to determine whether high fat high carbohydrate (HFHC) diet, Monosodium glutamate (MSG) diet or their combination is faster/more potent inducer of MS. Methods: Twenty male Sprague Dawley rats were randomly divided into four groups. Group 1 was given normal rat chow, group 2 was given HFHC diet, group 3 was given MSG in diet and group 4 was given both HFHC and MSG in their diet for 20 weeks. Body weight, blood pressure, lipid profile and glycaemic indices were determined at the end of study. Results: After 20 weeks of study, HFHC and MSG groups showed full blown Metabolic syndrome (MS) with development of obesity, hypertension, hyperglycaemia and dyslipidemia. However, group 4 which was given combination diet did not develop features of MS. Conclusion: Both HFHC and MSG containing diets when given alone are potent inducers of MS in rat model rather than their combination. Pak J Physiol 2022;18(2):6?9

Shensong Yangxin attenuates metabolic syndrome-induced atrial fibrillation via inhibition of ferroportin-mediated intracellular iron overload

BackgroundShensong Yangxin (SSYX) is a traditional Chinese medicine been widely used clinically to treat various arrhythmias including atrial fibrillation (AF). However, the role and precise mechanism of SSYX in MS-induced AF have not yet been elucidated. PurposeTo elucidate the protective effects of SSYX on MS-induced AF and its possible mechanisms of action. MethodsMale Wistar rats (180–220 g) were fed a 16-week high-carbohydrate, high-fat (HCHF) diet together with 25% fructose in drinking water to produce a MS model. Low-concentration (SSYX-L, 0.4 g/kg) and high-concentration (SSYX-H, 0.8 g/kg) of SSYX were given by daily gavage 8-weeks following HCHF diet for 8-weeks. In vivo electrophysiological study, histological analysis, RNA-sequence (RNA-Seq) and gene ontology (GO) analysis, qRT-PCR and western blot were performed. ResultsBoth low-concentration and high-concentration of SSYX could inhibit MS-induced AF susceptibility, electrical remodeling and structural remodeling. Results from RNA-sequence analysis revealed intracellular iron homeostasis mediated the protective effect of SSYX against MS. In vivo and in vitro experiments both demonstrated that SSYX up-regulated ferroportin (Fpn) expression and ameliorated intracellular iron overload induced by MS. To verified whether Fpn is the target of SSYX and intracellular iron overload mediated the protective effect of SSYX against MS, adeno-associated virus type 9 (AAV9) delivery system was used. Knocking down Fpn (AAV9-shFpn) markedly aggravated the reactive oxygen species (ROS) production, electrical remodeling and atrial fibrosis induced by MS, leading to a further increase of AF susceptibility induced by MS. ConclusionOur study demonstrated for the first time that SSYX reduced AF susceptibility, inhibited electrical remodeling and structural remodeling via up-regulating Fpn, decreasing intracellular iron overload and reducing ROS production. These results suggest that SSYX might be a potential therapeutic agent for the treatment of MS-induced AF.

Ingestion of orange juice prevents hyperglycemia and increases plasma miR-375 expression

The intake of high-fat, high-carbohydrate (HFHC) meals is associated with an increased risk of type 2 diabetes. There is evidence that the association of orange juice to a HFHC meal can modulate the expression of microRNAs (miRNAs) linked to pancreatic β-cell function such as miR-375. We evaluated the effect of a commercial orange juice intake with HFHC meal on plasma miRNAs expression in twelve healthy subjects in a crossover design study. Subjects ingested water, orange juice, or an isocaloric beverage along with a 1037kcal HFHC meal. Blood glucose and miRNAs were evaluated at baseline and 1, 3, and 5h after the intake. The area under the curve (AUC) for glycemia after ingestion of HFHC+orange juice did not differ from ingestion of HPHC+glucose or HFHC+water. However, the AUC was higher in HFHC meal+glucose compared to HFHC meal+water (p=0.034). Glucose and insulin concentrations were significantly higher in HFHC meal+glucose group after 1h, when compared with other groups and times (p<0.001). There was an increase in plasma miR-375 expression after 3h of ingestion of HFHC+orange juice versus water (p=0.026), and a decrease in plasma miR-205-5p expression after HFHC meal+glucose versus water (p=0.023). A single HFHC meal+orange juice modulated plasma miR-375 expression, which is a biomarker of pancreatic β-cell function, and contributed to preventing hyperglycemia.