Zucker Fatty Rats Research Articles

Dietary Sphingolipids Ameliorate Disorders of Lipid Metabolism in Zucker Fatty Rats

Dietary sphingolipids (SL) inhibit colon carcinogenesis, reduce serum cholesterol, and improve skin barrier function and are considered to be "functional lipids". For comparative determination of the effects of SL with different chemical compositions on lipid metabolism and its related hepatic gene expression, Zucker fatty rats were fed pure sphingomyelin (SM) of animal origin and glucosylceramide (GC) of plant origin. After 45 days, the SM and GC diets led to significant reductions in hepatic lipid and plasma non-HDL cholesterol. Both SM and GC diets decreased plasma insulin levels, whereas only the GC diet increased the plasma adiponectin level. Hepatic gene expression analysis revealed increased expression of adiponectin receptor 2 (Adipor2), peroxisome proliferator-activated receptor alpha (PPARalpha), and pyruvate dehydrogenase kinase 4 (Pdk4). However, expression of stearoyl CoA desaturase (Scd1) was significantly decreased. These results suggest that dietary SL, even of different origins and chemical compositions, may prevent fatty liver and hypercholesterolemia through improvement of adiponectin signaling and consequent increases in insulin sensitivity.

My favorite pyruvate carboxylase

Having completed a PhD in molecular and cellular biology in mammalian reproduction at the University of Sydney, my first postdoctoral appointment began early in 1965 in the laboratory of Sir Hans Krebs at Oxford University where I had the pleasure of working with Dr Eric Newsholme on the regulation of gluconeogenesis and glycolysis during fetal development. My introduction to Pyruvate Carboxylase (PC) came early in 1966 when Michael Scrutton arrived back in Oxford to submit his D.Phil. thesis after spending a remarkably productive time working on PC in the laboratory of its discoverer, Professor Merton Utter, at Western Reserve University Medical School, Cleveland, Ohio. Not surprisingly, Michael bubbled with infectious enthusiasm about PC, and presented an outstanding seminar to the Department. In late 1966 I moved to Professor Utter’s group and had an invaluable and enjoyable experience broadening my skills and filling some of the many gaps in my knowledge, particularly in biophysical techniques. The co-discoverer of PC, Professor Bruce Keech, returned to Cleveland in 1968 on sabbatical leave from the University of Adelaide, Australia, and we soon established an effective and agreeable collaboration. This collaboration was renewed in late 1969 when I arrived in Adelaide, where I secured a Faculty position in 1970, and continued until Bruce retired in 1983.

Treatment of the post-ischaemic inflammatory syndrome of diabetic nephropathy

Diabetes mellitus and its complications are a public health problem of epidemic proportions. Both diabetes and chronic kidney disease (CKD) increase the risk of acute kidney injury (AKI). Months after a single episode of acute ischaemia to the diabetic kidney, we have found an accelerated progression of nephropathy, with impaired function, severe renal inflammation, microvascular dysfunction, fibrosis and apoptotic cell death. We termed this entity the post-ischaemic inflammatory syndrome. We now test the hypothesis that blocking inflammation ameliorates the post-ischaemic inflammatory syndrome. Obese-diabetic ZS rats (F(1) hybrids of spontaneously hypertensive heart failure and Zucker fatty diabetic rats) were treated with mycophenolate mofetil (MMF), subjected to renal ischaemia or sham surgery, and monitored via the powerful technique of intravital microscopy. Amelioration of post-ischaemia inflammation with MMF therapy improved long-term renal function, microvascular dysfunction, fibrosis and apoptosis. These data support the hypothesis that the post-ischaemic inflammatory syndrome accelerates diabetic CKD, is a critical determinant of injury, and can be successfully treated.

Correction: Waves of Adipose Tissue Growth in the Genetically Obese Zucker Fatty Rat

This article has been republished because Figures 1-4 were originally published in the incorrect order.

Zucker fatty rat hepatocytes have impaired regulation of gene expression mediated by insulin and retinoids

The mechanism of insulin resistance at gene expression level is still unrevealed. We demonstrated retinoids synergize with insulin (INS) to induce glucokinase (Gck) expression in primary hepatocytes, showing their roles in modulating insulin action. Herein, we compared the responses of Gck, Srebf‐1c, Pck1 and Pklr in hepatocytes isolated from Zucker lean (ZL) and fatty (ZF) rats to INS (0 to 100nM) without or with 5 uM all trans retinoic acid (RA). The mRNA levels of these genes were analyzed by real time PCR. For Gck, RA started to synergize with INS at 1nM to induce its expression in ZL and ZF hepatocytes, but the induction folds by INS were higher in ZL than in ZF cells with or without RA. The Srebf‐1c mRNA was only induced in ZL, but not ZF hepatocytes. The Pck1 mRNA levels were decreased more in ZL than in ZF cells by 1 and 10nM INS without RA, and by 1nM INS with RA. The Pklr mRNA level was higher in ZF cells at basal state. It was not responsive to INS, RA or INS + RA in both ZL and ZF hepatocytes. We showed here ZL hepatocytes respond to INS and RA more robustly in regulation of gene expression than ZF cells, suggesting a potential model to study insulin resistance at gene expression level.Grant Funding Source: American Heart Association

Zucker lean and fatty rat hepatocytes respond differently to insulin and retinoids in the expression of glucose and lipid metabolic genes

We found that retinoids synergized with insulin to induce glucokinase gene (Gck) expression in primary hepatocytes, indicating their roles in modulating insulin sensitivity. Whether any change of this synergy exists in insulin resistant animals is unknown. The expression levels of Gck, Srebf‐1c, Pck1 and Fas in hepatocytes isolated from Zucker lean (ZL, insulin sensitive) and fatty (ZF, insulin resistant) rats in response to increasing concentrations of all trans retinoic acid (RA) with or without 1 nM insulin were analyzed by real time PCR. For Gck, RA started to induce its expression at 0.1 uM and 3uM, and synergized with insulin in ZL and ZF hepatocytes, respectively. The Srebf‐1c mRNA was induced by RA at 0.1 uM and insulin in ZL, but not ZF hepatocytes. The Pck1 mRNA was induced by RA at 0.1uM or higher in both ZL and ZF hepatocytes. Insulin‐mediated suppression of Pck1 expression was attenuated by RA at 3uM in ZL, but not ZF cells. Fas mRNA was not affected by RA in both ZL and ZF hepatocytes after 6 hours of treatment. Our results showed that ZL and ZF hepatocytes respond differently to insulin and RA treatments, suggesting alterations of RA responses in liver of insulin resistant rats.Grant Funding Source: AHA

Tart cherry intake reduces plasma and tissue inflammation in obesity‐prone rats

Obesity involves chronic inflammation, which may contribute to cardiovascular disease Previous studies show that diet provision of anthocyanin‐rich extracts can reduce inflammation. Our group tested the dietary relevance of these findings using a whole‐foods approach with anthocyanin‐rich tart cherries. We compared the effects of tart cherry‐enriched diets in obesity‐prone Zucker Fatty rats fed a pair‐fed a higher fat diet (47% of kcal) supplemented with either 1% freeze‐dried tart cherry powder or 0.85% extra carbohydrate (1:1 glucose:fructose). After 90 days, cherry intake significantly reduced serum glucose, triglycerides, cholesterol, and plasma tumor necrosis factor‐α and interleukin‐6. Cherry intake also reduced body weight, total fat mass and abdominal fat pad weight while increasing lean body mass. In addition, cherry decreased abdominal fat pad NFκB activity, TNF‐α mRNA and TNF‐α protein. Finally, cherry intake reduced cardiac NFκB activity, TNF‐α mRNA and TNF‐α protein. In obese rats, tart cherry‐enriched diets reduce plasma inflammation, abdominal fat inflammation, and cardiac inflammation, known risk factors for cardiovascular disease.

Regular Grape Intake Reduces Cardiac and Renal Dysfunction and Metabolic Syndrome in Obesity‐Prone Rats

Metabolic Syndrome is characterized by increased systemic inflammation, abdominal fat, high triglycerides, low HDL, hypertension, and insulin resistance. The presence of some or all of these risk factors predisposes one to Type II diabetes and cardiovascular disease. Epidemiologic studies suggest that higher intake of fruits/vegetables could modify risk factors for metabolic syndrome. Phytochemicals may be vital to the observed health effects. Grapes are a rich, whole‐food source of phytochemicals. In the obesity‐prone Zucker Fatty rat, we tested the effect of a higher fat diet(45% kcal) with added whole table grape powder(3% w:w). Rats were fed for 90 days. Compared to a macronutrient and calorie‐matched control group, the grape diet had no significant effect on body weight or DEXA‐determined body composition. Grape intake reduced blood pressure and proteinuria while improving cardiac output. The grape‐fed group had reduced heart weight, kidney weight, and liver weight. The grape‐fed animals had reduced fasting serum triglycerides and hyperinsulinemia but not total cholesterol(p=0.12). Finally, grape intake reduced plasma inflammatory markers C‐reactive protein, TNF‐α and IL‐6, and reduced plasma oxidative stress marker 8‐isoprostane. The results suggest that regular intake of grapes reduced several risk factors for cardiovascular disease and metabolic syndrome.

Physiologic and Pharmacologic Modulation of Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Expression in β-Cells by Peroxisome Proliferator–Activated Receptor (PPAR)-γ Signaling

OBJECTIVEWe previously showed that peroxisome proliferator–activated receptor (PPAR)-γ in β-cells regulates pdx-1 transcription through a functional PPAR response element (PPRE). Gene Bank blast for a homologous nucleotide sequence revealed the same PPRE within the rat glucose-dependent insulinotropic polypeptide receptor (GIP-R) promoter sequence. We investigated the role of PPARγ in GIP-R transcription.RESEARCH DESIGN AND METHODSChromatin immunoprecipitation assay, siRNA, and luciferase gene transcription assay in INS-1 cells were performed. Islet GIP-R expression and immunohistochemistry studies were performed in pancreas-specific PPARγ knockout mice (PANC PPARγ−/−), normoglycemic 60% pancreatectomy rats (Px), normoglycemic and hyperglycemic Zucker fatty (ZF) rats, and mouse islets incubated with troglitazone.RESULTSIn vitro studies of INS-1 cells confirmed that PPAR-γ binds to the putative PPRE sequence and regulates GIP-R transcription. In vivo verification was shown by a 70% reduction in GIP-R protein expression in islets from PANC PPARγ−/− mice and a twofold increase in islets of 14-day post-60% Px Sprague-Dawley rats that hyperexpress β-cell PPARγ. Thiazolidinedione activation (72 h) of this pathway in normal mouse islets caused a threefold increase of GIP-R protein and a doubling of insulin secretion to 16.7 mmol/l glucose/10 nmol/l GIP. Islets from obese normoglycemic ZF rats had twofold increased PPARγ and GIP-R protein levels versus lean rats, with both lowered by two-thirds in ZF rats made hyperglycemic by 60% Px.CONCLUSIONSOur studies have shown physiologic and pharmacologic regulation of GIP-R expression in β-cells by PPARγ signaling. Also disruption of this signaling pathway may account for the lowered β-cell GIP-R expression and resulting GIP resistance in type 2 diabetes.

Hyperglycemia attenuates acute permeability response to advanced glycation end products in retinal microvasculature

Increased microvascular permeability contributes to the development of diabetic retinopathy and is associated with hyperglycemia and accumulation of advanced glycation end products (AGEs). The isolated perfused retina preparation was used to investigate the effects of hyperglycemia (HG) on the permeability response to AGEs. Retinae were dissected from rats, and the vasculature perfused with sulforhodamine B fluorescent dye and permeability of venular capillaries was determined from the rate of decrease of fluorescence gradient across a vessel during stasis. The resting permeability was very high in streptozotocin treated and some obese Zucker fatty diabetic rats, but low in others. The permeability response to glycated albumin (which is free radical-dependent) in these animals was reduced for a range of concentrations compared to the lean controls. The effects of 15min 25mM glucose (HG) superfusion on the retinal microvascular permeability response to 5µM AGE-BSA was studied in non-diabetic Wistar rats. HG itself had no effect on permeability, but reduced the response to AGE-BSA from 1.02±0.08×10−6cms−1 to 0.31±0.07×10−6cms−1. The response to bradykinin (also free radical-dependent) was not affected by HG. This suggests that chronic exposure to HG down-regulates the signalling pathways activated in response to RAGE stimulation.

The synthetic GLP-I receptor agonist, exenatide, reduces intimal hyperplasia in insulin resistant rats

We studied the effect of a synthetic GLP-1 receptor agonist, exenatide, a drug approved for the treatment of type 2 diabetes, on the recovery from vascular injury in Zucker (non-diabetic) fatty rats. Exenatide 5.0 microg/kg per day or saline was administered for seven days before, and 21 days after balloon catheter mediated carotid injury. A pair feeding experiment helped differentiate between the drug itself and the known effects of the drug on decreased food intake. Body weight and glucose (weekly), carotid artery I/M ratio, aortic protein eNOS and NFkappaB-p65 were measured. Body weight gain in exenatide rats was significantly lower (53+/-5 vs. 89+/-8 g) than controls. Blood glucose did not change significantly. The I/M ratio in the exenatide group was 0.2+/-0.1 vs. 0.9+/-0.1 in controls (p<0.05). The expression of aortic eNOS was unchanged in exenatide treated rats and a small decrease seen in NFkappaB-p65 expression was not statistically significant. We conclude that exenatide attenuates intimal hyperplasia following balloon catheter induced vascular injury independently of glucose regulation and food intake. Our findings provide additional support for cardiovascular benefits of exenatide, especially in obese and pre-diabetic patients. Further research is needed to elucidate the mechanism underlying these effects.

Effects of periodontitis on aortic insulin resistance in an obese rat model

The combination of obesity and its associated risk factors, such as insulin resistance and inflammation, results in the development of atherosclerosis. However, the effects of periodontitis on atherosclerosis in an obese body remain unclear. The aim of the study was to investigate the effects of ligature-induced periodontitis in Zucker fatty rats on initiation of atherosclerosis by evaluating aortic insulin resistance. Zucker fatty rats (n=24) were divided into two groups. In the periodontitis group, periodontitis was ligature-induced for 4 weeks, whereas the control group was left unligated. After the 4-week experimental period, descending aorta was used for measuring the levels of lipid deposits, immunohistochemical analysis, and evaluation of gene expression. Levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and insulin were also measured. Rats in the periodontitis group had significantly enhanced lipid deposits in the aorta, but not in the control group. Expression of suppressor of cytokine signaling 3, vascular cell adhesion molecule 1, reactive oxygen species, nitrotyrosine, and endothelin-1 in the periodontitis group was more intense than that in the control group. Significantly decreased levels of phosphatidylinositol 3-kinase (Pi3k) catalytic β-polypeptide (Pi3kcb), Pi3kp85, and insulin receptor substrate 1 and 2 were observed in the periodontitis group. Levels of serum CRP and TNF-α were significantly increased in the periodontitis group. Under insulin-stimulated conditions, aorta in the periodontitis group altered the Akt phosphorylation. Periodontitis in obesity induced the initial stage of atherosclerosis and disturbed aortic insulin signaling.

Waves of Adipose Tissue Growth in the Genetically Obese Zucker Fatty Rat

BackgroundIn mammals, calories ingested in excess of those used are stored primarily as fat in adipose tissue; consistent ingestion of excess calories requires an enlargement of the adipose tissue mass. Thus, a dysfunction in adipose tissue growth may be a key factor in insulin resistance due to imbalanced fat storage and disrupted insulin action. Adipose tissue growth requires the recruitment and then the development of adipose precursor cells, but little is known about these processes in vivo.MethodologyIn this study, adipose cell-size probability distributions were measured in two Zucker fa/fa rats over a period of 151 and 163 days, from four weeks of age, using micro-biopsies to obtain subcutaneous (inguinal) fat tissue from the animals. These longitudinal probability distributions were analyzed to assess the probability of periodic phenomena.ConclusionsAdipose tissue growth in this strain of rat exhibits a striking temporal periodicity of approximately days. A simple model is proposed for the periodicity, with PPAR signaling driven by a deficit in lipid uptake capacity leading to the periodic recruitment of new adipocytes. This model predicts that the observed period will be diet-dependent.

The prostacyclin analog beraprost sodium ameliorates characteristics of metabolic syndrome in obese Zucker (fatty) rats.

OBJECTIVEThe prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications).RESEARCH DESIGN AND METHODSObese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg · kg−1 · day−1 b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed.RESULTSBPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post–glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-β-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS.CONCLUSIONSBPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.

Endothelial and Vascular Muscle PPARγ in Arterial Pressure Regulation

Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcription factor belonging to the retinoic acid receptor and thyroid hormone receptor family of nuclear receptors. Classically, these transcription factors regulate expression of target genes by binding to PPAR response elements (PPRE) in the 5′ flanking region of target genes as a heterodimer with retinoid X receptors (RXR). PPARγ first gained prominence when it was discovered that it was expressed specifically in adipocytes and its expression induced their differentiation.1 It has now become clear that although expression of PPARγ may be the highest in adipose tissue, it is expressed in many, if not all, cell types and tissues. Among the many roles ascribed to PPARγ are adipogenesis, insulin action, glucose homeostasis, and lipid metabolism. Other tissue-specific functions for PPARγ in liver, muscle, heart, macrophages, bone, and, more recently, the vasculature have been proposed, ascribed mainly from the analysis of cultured cells and a large and rapidly expanding set of tissue-specific PPARγ knockouts. The standing of PPARγ as a clinically important molecule emerged when it was discovered that PPARγ is the molecular target of the thiazolidinediones (TZD) class of antidiabetic agents.2 Although of understandable interest to diabetes researchers and clinicians, interest among “hypertensionists” increased when it became clear that TZD, in addition to improving glycemic control, tended to lower blood pressure. Many of these studies involved high-risk patients with diabetes or metabolic syndrome and an average decrease of ≈5 mmHg systolic blood pressure and 3 mmHg (diastolic blood pressure [DBP]) was typically reported. According to guidelines from the American Heart Association, 65 million Americans have hypertension and millions of others have prehypertension. Therefore, an analysis of any drug effective at lowering arterial pressure or physiological pathway targeted by that drug involved in regulating arterial pressure deserves serious attention. In this …

Differential effects of thiazolidinediones on adipocyte growth and recruitment in Zucker fatty rats.

BackgroundAdipose tissue grows by two mechanisms: hyperplasia (cell number increase) and hypertrophy (cell size increase). Thiazolidinediones are insulin-sensitizing peroxisome proliferator-activated receptor gamma agonists that are known to affect the morphology of adipose tissue.MethodologyIn this study, adipose cell-size probability distributions were measured in six Zucker fa/fa rats over a period of 24 days, from four weeks of age, using micro-biopsies to obtain subcutaneous (inguinal) fat tissue from the animals. Three of the rats were gavaged daily with rosiglitazone, a thiazolidinedione, and three served as controls. These longitudinal probability distributions were analyzed to obtain the rate of increase in cell-size diameter in rosiglitazone-treated animals, and the hyperplasia induced by treatment quantitatively.ConclusionsWe found that treatment leads to hypertrophy that leads to an approximately linear rate of cell diameter increase (2 m/day), and that the hyperplasia evident in treated animals occurs largely within the first eight days of treatment. The availability of additional lipid storage due to treatment may alleviate lipotoxicity and thereby promote insulin sensitivity. The hypothesis that a TZD regimen involving repeated treatments of limited duration may suffice for improvements in insulin sensitivity merits further investigation.

Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance.

Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes.

SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity

Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood. Here, we show that knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages broadly activates the JNK and IKK inflammatory pathways and increases LPS-stimulated TNFalpha secretion. Moreover, gene expression profiles reveal that SIRT1 knockdown leads to an increase in inflammatory gene expression. We also demonstrate that SIRT1 activators inhibit LPS-stimulated inflammatory pathways, as well as secretion of TNFalpha, in a SIRT1-dependent manner in RAW264.7 cells and in primary intraperitoneal macrophages. Treatment of Zucker fatty rats with a SIRT1 activator leads to greatly improved glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity during glucose clamp studies. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage proinflammatory state, fully consistent with the in vitro effects of SIRT1 in macrophages. In conclusion, these results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases.

미나리 줄기(Oenanthe javanica), 율무(Coicis lachryma-jobi L. var.), 차전자(Plantaginis asiatica L.) 물 추출물이 지질대사

The Nutraceutical Bio Brain Korea 21 Project Group, Kangwon National University, Gangwon 200-701, KoreaAbstractThis study was carried out to estimate beneficial effects of medicinal plant [Oenanthe javanica (MNR), Coicis lachryma-jobi L. var. (YM), Plantaginis asiatica L. (CJJ)] water extracts on activities of key enzymes such as lipoprotein lipase (LPL), acyl-CoA synthetase (ACS) and carnitine acetyltransferase (CAT) on lipid metabolism. LPL and ACS were extracted from the epididymal adipose tissue and liver of Zucker lean rats (lean) and Zucker fatty rats (fa/fa). MNR or YM water extract treatment significantly reduced the activity of lean and fa/fa LPL. When 10000 ppm of MNR, YM, and CJJ water extracts were tested, they decreased fa/fa LPL activity by 32.5%, 30.1% and 22.8%, respectively. The lean ACS activity was significantly higher in YM water extract treatment compared to the control and the MNR water extract treatment significantly increased the activity of fa/fa ACS, compared to the activity in the control (p<0.05). MNR water extract activated fa/fa ACS activity by 12-fold compared with control at 10000 ppm concentration. CAT activity was significantly higher in 10000 ppm and 20000 ppm CJJ water extract treatment than in the control. Thus, the MNR, YM and CJJ water extracts may have beneficial effects due to activities of enzymes related with fat metabolism in obese humans.Key words: obesity, acyl-CoA synthetase, lipoprotein lipase, carnitine acetyl transferase, medicinal plant

Nesfatin-1-Regulated Oxytocinergic Signaling in the Paraventricular Nucleus Causes Anorexia through a Leptin-Independent Melanocortin Pathway

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.