ABSTRACT
AIM: Antioxidant therapy for with vitamin E appears to be effective for the treatment of nonalcoholic fatty liver diseaseã(NAFLD). However, the mechanism of action and optimal therapeutic dosage is unclear. The present study was undertaken to examine whether the effects of α-tocopherol (α-Toc) on NAFLD are dose-dependent in a diet-induced obese model. METHODS: Male mice were fed standard chow, high-fat (HF) diet, HF diet with low-dose, or with high dose of α-Toc supplementation. Histological findings, triglyceride content, and the levels of protein expression related to fatty acid synthesis/oxidation such as carnitine palmitoyltransferase I (CPT-1) of liver were evaluated. In addition, 2-tetradecylglycidic acid (TDGA), a CPT-1 inhibitor, was administered to mice fed HF diet with low-dose of α-Toc. Finally, HepG2 cells in fat-loaded environment were treated with 0-50 µM α-Toc. RESULTS: Treatment of low-dose of α-Toc decreased HF-induced hepatic fat accumulation, but this finding was not observed in treatment of high dose of α-Toc. HF-induced reduction of CPT-1 was attenuated with low-dose of α-Toc but not with high dose of α-Toc. TDGA suppressed the improvement of histological findings in liver induced by low-dose of α-Toc treatment. CPT-1 expression in HepG2 cells increased in response to low-dose of α-Toc, but not in high dose. CONCLUSIONS: Dual action of α-Toc on CPT-1 protein levels was observed. The effect of vitamin E on NAFLD may be not be dose-dependent.
ABSTRACT
INTRODUCTION: Endoscopic intragastric balloon (IGB) placement has been performed in Japan since 2004. The nationwide surveys were repeatedly carried out to confirm the effectiveness and safety of IGB in Japan. We herein present the accumulated results. METHODS: Twenty-six Japanese endoscopists personally imported products of the BioEnterics Intragastric Balloon (BIB)/Orbera system after completing the training courses in Japan. Mail surveys were posted to them every 2 years from 2010. This study included the accumulated data of the six surveys, and excluded data from non-Japanese patients and the Orbera365 data. RESULTS: Between 2004 and 2019, 399 obese Japanese patients underwent IGB treatment using the BIB/Orbera system. The incidence rates of early removal of IGB within 1 week and complications due to IGB were 4.8% and 6.1%, respectively. The average percent excess weight loss (%EWL) and percent total weight loss (%TWL) at IGB removal were 46.6% and 11.5%, and successful weight loss, defined as %EWL ≥ 25% or %TWL ≥ 10%, was achieved in 65.6% or 54.5% of the patients, respectively. Multivariate analyses revealed that older age and larger saline filling volume were independent predictors of successful weight loss. At 1 year after IGB removal, successful weight loss defined by the %EWL and %TWL was maintained in 44.7% and 34.1% of the patients, respectively. CONCLUSION: IGB therapy using the BIB/Orbera system has been safely and effectively performed in Japan. The successful weight loss may be associated with older age and larger saline filling volume.
Subject(s)
Gastric Balloon , Obesity/surgery , Adult , Body Mass Index , Device Removal , Female , Gastroscopy , Humans , Japan , Male , Middle Aged , Treatment Outcome , Weight LossABSTRACT
We report the identification of a mutation in the solute carrier family 5 member 2 (SLC5A2) gene, which encodes sodium-glucose cotransporter 2, in a family with familial renal glucosuria. The proband was a 26-year-old Japanese man referred to the diabetes division with repeated glucosuria without hyperglycemia. His mother, uncle and grandfather also had a history of glucosuria. A heterozygous missense mutation (c.303T>A:p.N101K) in SLC5A2 was identified in the patient and his mother, but not in 200 chromosomes from 100 healthy and unrelated individuals, or in 3,408 Japanese individuals in the Tohoku Medical Megabank. Furthermore, bioinformatics software predicted that this lesion would be pathogenic. We infer that the mutation led to clinically relevant sodium-glucose cotransporter 2 dysfunction. The patient showed no symptoms of hypoglycemia, but continuous glucose monitoring confirmed asymptomatic hypoglycemia.
Subject(s)
Glycosuria, Renal/genetics , Sodium-Glucose Transporter 2/genetics , Adult , Asian People/genetics , Family , Female , Heterozygote , Humans , Japan , Male , Mutation, Missense , PedigreeABSTRACT
We examined whether glucagon-like peptide-1 (GLP-1) affects ß-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic ß-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in ß-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.
Subject(s)
Diet, High-Fat/adverse effects , Glucagon-Like Peptide 1/administration & dosage , Hypothalamus/metabolism , Insulin-Secreting Cells/cytology , Neural Pathways/drug effects , Obesity/drug therapy , Animals , Brain-Derived Neurotrophic Factor/metabolism , Cell Proliferation/drug effects , Cell Size/drug effects , Glucagon-Like Peptide 1/pharmacology , Glucose/metabolism , Glucose Intolerance/drug therapy , Glucose Intolerance/etiology , Hypothalamus/drug effects , Injections, Intraperitoneal , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Liraglutide/administration & dosage , Liraglutide/pharmacology , Obesity/chemically induced , Obesity/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Sympathectomy , VagotomyABSTRACT
Obesity can be associated with systemic low-grade inflammation that leads to obesity-related metabolic disorders. Recent studies raise the possibility that the inflammation in hypothalamus, liver and white adipose tissue (WAT) contributes to the pathogenesis of diet-induced obesity. We focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine produced from spleen in obesity because it is indicated that obesity decreases the expression of pro-inflammatory cytokines in spleen. Obesity results in decrease of IL-10 synthesis from spleen, probably due to reduction of B-cells expression by promoting oxidative stress and apoptosis in spleen. Splenectomy (SPX) aggravates the inflammatory response in hypothalamus, liver and WAT. These SPX-induced alterations are inhibited by systemic administration of IL-10. Moreover, in IL-10 deficiency, SPX had little effect on the inflammatory responses in these multiple organs. We show the role of spleen-derived IL-10 on inflammatory responses in obesity.
Subject(s)
Inflammation/prevention & control , Interleukin-10/physiology , Obesity/complications , Spleen/metabolism , Adipose Tissue/metabolism , Animals , Cytokines/metabolism , Humans , Inflammation/etiology , Inflammation/metabolism , Obesity/metabolism , Spleen/pathologyABSTRACT
Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulin-dependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Diabetes Mellitus, Type 1/chemically induced , Programmed Cell Death 1 Receptor/immunology , Diabetes Mellitus, Type 1/immunology , Female , Humans , Melanoma/drug therapy , Middle Aged , Nivolumab , Treatment OutcomeABSTRACT
Stress-induced inflammatory responses in the portal system are characterized by elevations in serum concentrations of interleukin-6 (IL-6) and endotoxins such as lipopolysaccharides (LPS). LPS translocation from the intestinal to the capillary lumen occurs via LPS endocytosis by the capillary endothelium. Because the capillary endothelium of the small intestinal submucosa is fenestrated, we determined the role of pore modifications within the fenestrated endothelium in relaying inflammatory stress responses in the portal vein. We evaluated changes in the diameter and density of endothelial pores of the lamina propria of intestinal villi induced by continuous light (CL) exposure for 48 h and the correlation between these changes and serum IL-6 concentration in the portal vein in a rat model. We found significant increases in both the pore diameter and density, accompanied by a significant increase in portal IL-6 concentration; these changes were significantly attenuated by pretreatment with propranolol, a beta adrenergic receptor antagonist. In contrast, intravenous noradrenaline administration mimicked CL-induced modifications of the diameter and density of pores and the elevation of portal vein IL-6 concentration. These findings suggested that stress-induced inflammatory responses in the portal system may be a part of the modifications of the endothelial pores triggered by sympathetic activation.
Subject(s)
Capillaries/pathology , Capillaries/ultrastructure , Endothelium, Vascular/pathology , Endothelium, Vascular/ultrastructure , Stress, Psychological/pathology , Animals , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Intestinal Mucosa/blood supply , Male , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Rats , Rats, WistarABSTRACT
BACKGROUND: Human thoracic brown adipose tissue (BAT), composed of several subdivisions, is a well-known target organ of many clinical studies; however, the functional contribution of each part of human thoracic BAT remains unknown. The present study analyzed the significance of each part of human thoracic BAT in the association between regional distribution, cellularity, and factors involved in the functional regulation of thoracic BAT. METHODS: We analyzed 1550 healthy adults who underwent medical check-ups by positron-emission tomography and computed tomography (PET-CT) imaging, 8 cadavers, and 78 autopsy cases in an observational study. We first characterized the difference between the mediastinum and the supraclavicular areas using counts of BAT detection and conditions based on PET-CT outcomes. The measurable important area was then subjected to systematic anatomical and immunohistochemical analyses using anti-uncoupling protein 1 (UCP1) antibody to characterize the cellularity in association with age and sex. RESULTS: In PET-CT scanning, the main site of thoracic BAT was the mediastinum rather than the supraclavicular area (P < 0.05). Systemic macroanatomy revealed that the thumb-sized BAT in the posterior mediastinal descending para-aortic area (paBAT) had feeding vessels from the posterior intercostal arteries and veins and sympathetic/parasympathetic innervation from trunks of the sympathetic and vagus nerves, respectively. Immunohistochemical analysis indicated that the paBAT exhibited immunoreactivity for tyrosine hydroxylase and vesicular acetylcholine transporter located in the pericellular nervous fibers and intracellular UCP1. The brown adipose cells of paBAT showed age-dependent decreases in UCP1 expression (P < 0.05), accompanied by a significant increase in vacuole formation, indicating fat accumulation (P < 0.05), from 10 to 37 years of age (P < 0.01). CONCLUSIONS: paBAT may be one of the essential sites for clinical application in BAT study because of its visible anatomy with feeding vessels and sympathetic/parasympathetic innervation functionally affected by outer condition and senescence.
Subject(s)
Adipose Tissue, Brown/diagnostic imaging , Para-Aortic Bodies/diagnostic imaging , Radiography, Thoracic , Thorax/metabolism , Adipose Tissue, Brown/cytology , Adolescent , Adult , Aged , Aged, 80 and over , Autopsy , Cadaver , Child , Female , Fluorodeoxyglucose F18 , Humans , Ion Channels/biosynthesis , Male , Middle Aged , Mitochondrial Proteins/biosynthesis , Para-Aortic Bodies/cytology , Positron-Emission Tomography , Thorax/cytology , Uncoupling Protein 1 , Vacuoles/metabolismABSTRACT
Nesfatin-1/NucB2, an anorexigenic molecule, is expressed mainly in the hypothalamus, particularly in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN). Nesfatin-1/NucB2 is also expressed in the subfornical organ (SFO). Because the SON and PVN are involved in body fluid regulation, nesfatin-1/NucB2 may be involved in dehydration-induced anorexia. To clarify the effects of endogenous nesfatin-1/NucB2, we studied changes in nesfatin-1/NucB2 mRNA levels in the SFO, SON, and PVN in adult male Wistar rats after exposure to osmotic stimuli by using in situ hybridization histochemistry. Significant increases in nesfatin-1/NucB2 mRNA levels, â¼2- to 3-fold compared with control, were observed in the SFO, SON, and PVN following water deprivation for 48 h, consumption of 2% NaCl hypertonic saline in drinking water for 5 days, and polyethylene glycol-induced hypovolemia. In addition, nesfatin-1/NucB2 expression was increased in response to water deprivation in a time-dependent manner. These changes in nesfatin-1/NucB2 mRNA expression were positively correlated with plasma sodium concentration, plasma osmolality, and total protein levels in all of the examined nuclei. Immunohistochemistry for nesfatin-1/NucB2 revealed that nesfatin-1/NucB2 protein levels were also increased after 48 h of dehydration and attenuated by 24 h of rehydration. Moreover, intracerebroventricular administration of nesfatin-1/NucB2-neutralizing antibody after 48 h of water deprivation resulted in a significant increase in food intake compared with administration of vehicle alone. These results suggested that nesfatin-1/NucB2 is a crucial peptide in dehydration-induced anorexia.
Subject(s)
Anorexia/etiology , Calcium-Binding Proteins/metabolism , DNA-Binding Proteins/metabolism , Dehydration/physiopathology , Nerve Tissue Proteins/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Supraoptic Nucleus/metabolism , Animals , Anorexia/metabolism , Dehydration/complications , Eating/physiology , Male , Nucleobindins , RNA, Messenger/metabolism , Rats , Rats, Wistar , Sodium/blood , Water Deprivation/physiologyABSTRACT
We examined the effects of serotonin (5-HT) depletion induced by peripheral injection of 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) on the expression of feeding-regulating peptides expressions by using in situ hybridization histochemistry in adult male Wistar rats. PCPA pretreatment had no significant effect on basal levels of oxytocin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), pro-opiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART), neuropeptide-Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin in the hypothalamus. Food deprivation for 48 h caused a significant decrease in CRH, TRH, POMC, and CART, and a significant increase in NPY, AgRP and MCH. After PCPA treatment, POMC and CART did not decrease despite food deprivation. NPY was significantly increased by food deprivation with PCPA, but was attenuated compared to food deprivation without PCPA. These results suggest that the serotonergic system in the hypothalamus may be involved in the gene expression of POMC, CART, and NPY related to feeding behavior.
Subject(s)
Feeding Behavior , Food Deprivation , Hypothalamus/metabolism , Peptide Hormones/metabolism , Serotonin/deficiency , Animals , Body Weight , Eating , Enzyme Inhibitors/administration & dosage , Fenclonine/administration & dosage , Gene Expression Regulation , Hypothalamus/drug effects , Injections , Male , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neuropeptide Y/genetics , Neuropeptide Y/metabolism , Peptide Hormones/genetics , Pro-Opiomelanocortin/genetics , Pro-Opiomelanocortin/metabolism , Rats , Rats, Wistar , Time Factors , Tryptophan Hydroxylase/antagonists & inhibitors , Tryptophan Hydroxylase/metabolismABSTRACT
OBJECTIVE: Nonnutritive sweeteners (NNSs) have been studied in terms of their potential roles in type 2 diabetes, obesity, and related metabolic disorders. Several studies have suggested that NNSs have several specific effects on metabolism such as reduced postprandial hyperglycemia and insulin resistance. However, the detailed effects of NNSs on body adiposity and energy metabolism have not been fully elucidated. We investigated the effects of an NNS on energy metabolism in mice with diet-induced obesity (DIO). METHODS: DIO mice were divided into NNS-administered (4% NNS in drinking water), sucrose-administered (33% sucrose in drinking water), and control (normal water) groups. After supplementation for 4 weeks, metabolic parameters, including uncoupling protein (UCP) levels and energy expenditure, were assessed. RESULTS: Sucrose supplementation increased hyperglycemia, body adiposity, and body weight compared to the NNS-administered and control groups (P<0.05 for each). In addition, NNS supplementation decreased hyperglycemia compared to the sucrose-administered group (P<0.05). Interestingly, NNS supplementation increased body adiposity, which was accompanied by hyperinsulinemia, compared to controls (P<0.05 for each). NNS also increased leptin levels in white adipose tissue and triglyceride levels in tissues compared to controls (P<0.05 for each). Notably, compared to controls, NNS supplementation decreased the UCP1 level in brown adipose tissue and decreased O2 consumption in the dark phase. CONCLUSIONS: NNSs may be good sugar substitutes for people with hyperglycemia, but appear to influence energy metabolism in DIO mice.
Subject(s)
Adipose Tissue/drug effects , Adiposity/drug effects , Energy Metabolism/drug effects , Hyperinsulinism/chemically induced , Obesity/metabolism , Sweetening Agents/pharmacology , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Diet , Ion Channels/blood , Leptin/metabolism , Mice , Mitochondrial Proteins/blood , Obesity/etiology , Sucrose/pharmacology , Sweetening Agents/administration & dosage , Triglycerides/metabolism , Uncoupling Protein 1ABSTRACT
OBJECTIVE: Dipeptidyl peptidase (DPP)-4 is responsible for the degradation of several peptides that contain an alanine or proline at the penultimate position or position P1. DPP-4 inhibitors (DPP-4is) have protective effects against type-2 diabetes and several metabolic disorders. METHODS: In the present study, we examined the effects of des-fluoro-sitagliptin (DFS), a DDP-4i, on body adiposity and levels of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ coactivator-1 (PGC-1), and uncoupling proteins (UCPs) in mice with diet-induced obesity. RESULTS: Treatment with DFS dose-dependently decreased the weight of white adipose tissue and serum levels of glucose, compared with controls, without influencing food intake (P<0.05). Additionally, DFS treatment increased the levels of PPAR-α, PGC-1, and UCPs in brown adipose tissue (BAT), and of PPAR-α and UCP3 in skeletal muscle (P<0.05). Furthermore, the effects on BAT PGC-1 and muscle PPAR-α levels were attenuated by treatment with the glucagon-like peptide 1 (GLP-1) antagonist exendin (9-39). Interestingly, hypothalamic levels of proopiomelanocortin (POMC) were increased by DFS treatment and the effects of DFS on PPAR-α, PGC-1, and UCP levels were attenuated in melanocortin (MC)-4 receptor-deficient mice. CONCLUSIONS: In conclusion, high-dose DFS appeared to regulate body adiposity and UCPs in mice with diet-induced obesity, at least partly through a GLP-1 and/or MC-4 pathway.
Subject(s)
Adipose Tissue, Brown/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Ion Channels/metabolism , Mitochondrial Proteins/metabolism , Obesity/metabolism , Pyrazines/pharmacology , Triazoles/pharmacology , Adipose Tissue, Brown/drug effects , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Dietary Fats/adverse effects , Male , Mice , Mice, Inbred C57BL , PPAR gamma/metabolism , Sitagliptin Phosphate , Uncoupling Protein 1ABSTRACT
Cisplatin has been widely used; however, various disadvantageous side effects afflict patients. Rikkunshito (RKT), a traditional Japanese herbal medicine, has been widely prescribed in Japan to improve anorexia; but the mechanisms are unknown. Here we studied whether RKT could improve anorexia induced by cisplatin and changes in feeding-regulating peptides in the hypothalamus in rats. Adult male rats were divided into 4 groups: water+saline (WS), water+cisplatin (WC), RKT+saline (RS), and RKT+cisplatin (RC) groups. Water or RKT (1g/kg) was intragastrically administered for 4 days, from day -1 to day 2, and saline or cisplatin (6mg/kg) was intraperitoneally (i.p.) administered at day 0. After i.p. administration, cumulative food intake, water intake, urine volume and body weight were measured. The rats were then decapitated, followed by removal of the brain, and feeding-regulating peptides in the hypothalamus were measured by in situ hybridization histochemistry. In the three-day measurements, there were no significant changes in cumulative water intake and urine volume. The body weight and cumulative food intake in WC significantly decreased compared to WS, whereas these were not observed in RC. Pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the arcuate nucleus (ARC) in WC significantly increased, and neuropeptide Y (NPY) in the ARC decreased compared to WS, whereas those in RS and RC were comparable to WS. These results suggest that RKT may have therapeutic potential for anorexia induced by cisplatin.
Subject(s)
Anorexia/drug therapy , Drugs, Chinese Herbal/pharmacology , Nerve Tissue Proteins/metabolism , Neuropeptide Y/metabolism , Pro-Opiomelanocortin/metabolism , Animals , Anorexia/chemically induced , Anorexia/metabolism , Blood Glucose/drug effects , Body Weight/drug effects , Cisplatin , Eating/drug effects , Feeding Behavior/drug effects , Ghrelin/blood , Herbal Medicine , Hesperidin/pharmacology , Hypothalamus/drug effects , Hypothalamus/metabolism , Male , Plant Extracts/pharmacology , Rats , Rats, WistarABSTRACT
Brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild-type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1-R) in BDNF neurons. BDNF-induced feeding suppression was partially attenuated in rats pre-treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1-Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.
Subject(s)
Anorexia/physiopathology , Brain-Derived Neurotrophic Factor/physiology , Corticotropin-Releasing Hormone/physiology , Feeding Behavior/physiology , Histamine/physiology , Ventromedial Hypothalamic Nucleus/physiology , Animals , Anorexia/chemically induced , Body Weight/drug effects , Body Weight/physiology , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/pharmacology , Eating/drug effects , Eating/physiology , Feeding Behavior/drug effects , Histamine/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptors, Histamine H1/genetics , Receptors, Histamine H1/metabolism , Ventromedial Hypothalamic Nucleus/drug effectsABSTRACT
Animal models of obesity show that lipid deposits can injure the kidneys,and there is evidence for the role of lipids in the development of chronic renal dis-ease (CKD). Statins exhibit a lipid-lowering effect that acts on both total cholesterol and triglyceride (TG) levels and pleiotropic effects including their ability to reduce inflammation and fibrosis. The purpose of the present study was to confirm whether obesity induced by a high-fat diet (HFD, 60% fat) promotes lipid accumulation in the tubulointerstitial and/or glomerular areas in the kidney, and whether treatment of several statins, pravastatin (30 mg/kg, p.o.), rosuvastatin (3 mg/kg, p.o.),pitavastatin (1 mg/kg, p.o.) and atorvastatin (10 mg/kg, p.o.), suppresses obesity-induced lipid accumulation. Using male C57Bl/6J mice, we examined parameters related to energy metabolism, lipid accumulation as well as macrophage infiltration in glomeruli and the tubulointerstitial area, and glomerular injury using nephrin and desmin expression. None of the statins affected body weight, glucose metabolism,serum TG and adiponectin levels, or serum inflammatory cytokine levels. However,all statins improved lipid accumulation in the proximal tubules, improved glomerular hypertrophy, increased nephrin expression and decreased desmin expression, compared to non-treated obese animals. Moreover, the reduction of proximal tubular lipid accumulation was greater with pravastatin and rosuvastatin treatment than with pitavastatin and atorvastatin treatment. We concluded that hydrophilic statins may be more effective for preventing lipid accumulation in renal tubules than lipophilic statins.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Kidney Tubules/drug effects , Lipid Metabolism/drug effects , Obesity/physiopathology , Adiponectin/blood , Animals , Atorvastatin , Body Weight/drug effects , Cholesterol/blood , Cytokines/blood , Diet, High-Fat/adverse effects , Disease Models, Animal , Heptanoic Acids/pharmacology , Kidney Diseases/drug therapy , Kidney Diseases/etiology , Kidney Tubules/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/drug therapy , Pravastatin/pharmacology , Pyrroles/pharmacology , Quinolines/pharmacology , Triglycerides/bloodABSTRACT
The aim of the present study is to examine the effects of the antihypertensive drug cilnidipine on glucose metabolism and adipocytokines, including adiponectin, in diet-induced obese (DIO) mice. The effects of cilnidipine on insulin sensitivity and the levels of adiponectin in DIO mice were examined after the mice had been treated with cilnidipine dissolved in water at a dose of 0.2 g l(-1) for 14 days. As expected, treatment with cilnidipine decreased the systolic and diastolic blood pressures in DIO mice, compared with control mice (P<0.05 for each parameter). Cilnidipine treatment improved glucose and insulin sensitivity in DIO mice. In addition, cilnidipine treatment dramatically increased the level of adiponectin in white adipose tissue (P<0.05) and the circulating levels of total and high-molecular weight (HMW) adiponectin in DIO mice (P<0.01 for each parameter). Furthermore, the secretion of HMW adiponectin and the ratio of HMW adiponectin/total adiponectin were both increased after cilnidipine treatment. Finally, the secretion of adiponectin from adipocytes was increased after cilnidipine treatment. Taken together, these results indicate that cilnidipine improves insulin tolerance and adiponectin levels, especially high-molecular type adiponectin, in DIO mice.
Subject(s)
Adiponectin/metabolism , Calcium Channel Blockers/pharmacology , Diet, High-Fat/adverse effects , Dihydropyridines/pharmacology , Glucose/metabolism , Obesity/etiology , Obesity/metabolism , Adipocytes/drug effects , Adipocytes/metabolism , Adipocytes/pathology , Administration, Oral , Animals , Blood Pressure/drug effects , Calcium Channel Blockers/administration & dosage , Cells, Cultured , Dihydropyridines/administration & dosage , Disease Models, Animal , Insulin/metabolism , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , Obesity/pathology , Resistin/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen. METHODS: We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated. RESULTS: Obesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice. CONCLUSIONS: We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.
Subject(s)
Diet, High-Fat/adverse effects , Inflammation/etiology , Interleukin-10/physiology , Obesity/complications , Renal Insufficiency, Chronic/etiology , Spleen/metabolism , Splenectomy , Animals , Blood Pressure Determination , Blotting, Western , Cell Proliferation , Cytokines/metabolism , Female , Immunoenzyme Techniques , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/pathology , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology , Reverse Transcriptase Polymerase Chain Reaction , Spleen/pathologyABSTRACT
INTRODUCTION: Laparoscopic bariatric surgery has gradually spread in Japan since it was introduced in 2000. In 2005, we introduced laparoscopic adjustable gastric banding (LAGB) with the LAP-BAND system into Japan. Here, we evaluate our intermediate-term results with the LAP-BAND system. METHODS: Between August 2005 and June 2010, 27 Japanese patients with morbid obesity (BMI ≥ 35 kg/m(2) ) underwent LAGB with the LAP-BAND system in our institution. Our patients' average weight was 111 kg and BMI was 41 kg/m(2) . All LAGB procedures were performed through the pars flaccida pathway with band fixation using gastric-to-gastric sutures. The average follow-up period was 48 months. RESULTS: All procedures were completed laparoscopically. One early complication (sudden cardiac arrest due to postoperative bleeding) and three late complications (port trouble, megaesophagus, and band slippage) were experienced, and reoperations were performed in three of the patients. Weight loss and percentage of excess weight loss on average were 26 kg and 53% after 3 years and 22 kg and 53% after 6 years, respectively. In line with this good weight loss, comorbidities, especially those of type 2 diabetes and metabolic syndrome were frequently resolved or improved. CONCLUSION: LAGB with the LAP-BAND system appears to be beneficial in obese Japanese patients.