Preventive effect of embelin from embelia ribes on lipid metabolism and oxidative stress in high-fat diet-induced obesity in rats

A high-fat diet (HFD) results in hyperlipidemia and an increase in oxidative stress. The purpose of this study was to investigate the preventive effect of embelin against hyperlipidemia and oxidative stress in HFD-induced obesity in rats. Male Wistar rats aged 12 weeks (150-200 g) were fed with an HFD for a period of 28 days to induce experimental obesity. HFD-induced obese rats were treated with embelin (50 mg/kg) or orlistat (10 mg/kg) for 21 days. A range of parameters were tested including body weight gain, body mass index (BMI), blood pressure, visceral fat pad weights, serum levels of glucose, insulin, leptin, apolipoprotein B (ApoB), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hepatic thiobarbituric acid-reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Twenty-one days of embelin (50 mg/kg) treatment produced effects similar to orlistat in reducing body weight gain, blood pressure, visceral fat pad weight, serum lipid levels, as well as coronary artery risk and atherogenic indices of HFD-fed rats. Embelin treatment also lowered the serum levels of glucose by 24.77 %, insulin by 35.03 %, and leptin by 43.39 %. Furthermore, embelin treatment significantly (p < 0.01) decreased the hepatic TBARS levels, while increasing the SOD, CAT, and GSH levels in obese rats. The present study indicated the preventive effect of embelin in HFD-induced obesity and its related complications. Embelin could be valuable in the development of new drug therapies to prevent obesity, hyperlipidemia, and oxidative stress.     

Effects of chronic acarbose treatment on adipocyte insulin responsiveness, serum levels of leptin and adiponectin and hypothalamic NPY expression in obese diabetic Wistar rats

1. Inhibitors of intestinal glucosidases have been shown to improve glycaemic control in diabetic and obese humans and animals. In the present study, we have investigated the effect of 3 months treatment with acarbose on adiposity, food intake and the modulation of hypothalamic neuropeptide Y (NPY) in obese diabetic Wistar (WDF) rats and the possible correlation between changes in overall insulin sensitivity and the level of circulating adipokines, leptin and adiponectin. In addition, we investigated the effect of acarbose on adipocyte insulin signalling. 2. Mature male WDF rats were randomly distributed to one of three treatment groups (no acarbose or 20 or 40 mg of acarbose/100 g diet). After 3 months, blood glucose, cholesterol, triglyceride, insulin, leptin and adiponectin were analysed. Insulin signalling was determined in isolated adipocytes as the stimulation of mitogen-activated protein kinase (MAPK) and Akt phosphorylation; the level of hypothalamic NPY was assessed by immunohistochemistry. 3. Acarbose-treated rats had lower levels of blood glucose, cholesterol, triglyceride, insulin and leptin and an increase in adiponectin compared with untreated animals. There were no changes in bodyweight and adiposity. Stimulation of adipocyte MAPK activity by insulin was higher in rats treated with both doses of acarbose, whereas higher stimulation of Akt phosphorylation was observed with the highest dose of acarbose. Although food intake was not significantly reduced in rats treated with acarbose, the acarbose-treated rats had lower NPY expression in the arcuate nucleus. 4. We conclude that the improvement in overall insulin sensitivity in WDF rats after prolonged acarbose treatment is paralleled by increases in circulating adiponectin and adipocyte insulin responsiveness. Acarbose neither decreases food intake nor reverts obesity, but decreases leptin levels and the expression of the orexigenic NPY in the hypothalamus.     

Obesity-induced testicular oxidative stress,inflammation and apoptosis: Protective and therapeutic effects of orlistat

Obesity has been reported to induce oxidative stress, inflammation and apoptosis in the testis. The objective of this study was to determine the effects of the anti-obesity drug orlistat, on testicular oxidative stress, inflammation and apoptosis in high-fat diet (HFD)-fed rats. Twenty-four adult male Sprague Dawley rats weighing 250−300 g were randomized into four groups (n = 6/group), namely; normal control (NC), high-fat diet (HFD), HFD plus orlistat (10 mg/kg body weight/day administered concurrently for 12 weeks) (HFD + Opr) and HFD plus orlistat (10 mg/kg body weight/day administered 6 weeks after induction of obesity) (HFD + Ot) groups. Antioxidant enzymes activities were significantly decreased, while mRNA levels of pro-apoptotic markers (p53, Bax/BCl-2, caspase-9, caspase-8 and caspase-3) were significantly increased in the testis of HFD group relative to NC group. Furthermore, the mRNA levels of pro-inflammatory markers (nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis factor alpha and interleukin (IL)-1β increased significantly, while anti-inflammatory marker (IL-10) decreased significantly in the testis of the HFD group relative to NC group. However, in both models of orlistat intervention (protective and treatment models) up-regulated antioxidant enzymes, down-regulated inflammation and apoptosis were observed in the testis of HFD-fed rats. Orlistat ameliorated testicular dysfunction by attenuating oxidative stress, inflammation and apoptosis in HFD-fed rats, suggesting its potential protective and therapeutic effects in the testis compromised by obesity.     

Leptin potentiates the anti-obesity effects of rimonabant

We hypothesized that a combination of low doses of rimonabant and leptin would markedly reduce body weight through the modulation of neuronal activity within the hypothalamus. To this end, high fat diet-induced obese rats were randomized to receive either leptin (0.5mg/kg subcutaneously), rimonabant (3mg/kg), the combination of both, or vehicle, daily for a duration of 2 weeks. A subset of rats was pair-fed to the combination-treated animals and received either vehicle or leptin. At the end of the weight loss phase, leptin treatment was maintained for 7 days while rimonabant was discontinued to assess changes in body weight during the rebound phase. The combination of rimonabant and leptin resulted in a marked inhibition of food intake and a profound reduction in body weight that was greater than achieved with either leptin or rimonabant alone. Treatment with leptin during the rebound phase inhibited compensatory increases in body weight associated with restitution of ad libitum feeding in previously pair-fed rats. Moreover, leptin partially blunted the rebound in food intake and body weight associated with cessation of rimonabant therapy.To investigate the effect of the combination on neuronal firing in the rat hypothalamus, single unit activity was recorded from brain slices containing the ventromedial and arcuate nuclei. The combination of rimonabant and leptin synergistically increased and decreased neuronal firing in the ventromedial and arcuate nuclei, respectively. Overall, these data demonstrate profound anti-obesity effects of combining cannabinoid type 1 receptor antagonists and leptin.     

The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake

The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss. Diet-induced obese (DIO) rats were dosed with rimonabant (3, 10 mg/kg PO once daily) and matched with pair-fed controls. Food intake and body weight were measured daily. Blood samples and adipose tissue were collected on day 15 for measurement of plasma adiponectin and adiponectin mRNA levels. DIO rats treated with rimonabant and pair-fed controls showed very similar changes in body weight. Although tolerance developed to the anorectic effect of rimonabant, total food intake was significantly decreased over the 14-day study period and fully accounted for the observed reductions in body weight. Adiponectin mRNA and plasma adiponectin were elevated in vehicle-treated chow-fed animals compared to obese controls, and did not differ between rimonabant-treated and pair-fed animals. The similarities between rimonabant-treated and pair-fed animals in body weight loss and the absence of differences in measures of adiponectin activity between drug-treated and pair-fed animals suggest that the outcomes of this experiment were solely mediated by the drug-induced reduction in food intake.     

Therapeutic potential of orlistat - bupropion treatment on high fat diet-induced lipotoxicity

This study was designed to investigate the possibility of achieving a combined benefit of the therapeutic dose of orlistat and half that of bupropion treatment on some obesity related parameters in high fat diet (HFD)-induced obesity model. Female C57BL/6 mice were fed HFD ad libitum for 8 weeks, then treated with either orlistat (10 mg/kg, p.o. daily), bupropion (30 mg/kg, p.o daily) or their combined treatment for 4 weeks. The results revealed that HFD induced increases in obesity related parameters (body and fat weights, adipocyte size, lipid profile, leptin level, liver nitrate/nitrite content, hepatic fatty changes and bone marrow adipoblasts). The changes in lipid profile included cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels. Although drugs regimen duration was short, the findings demonstrated ameliorative effect of the combined treatment on all studied parameters with more pronounced effect on adipocyte size, liver and bone marrow histology.     

脂肪细胞因子与肥胖和糖尿病的关系

目的 探讨腹脂素等脂肪细胞因子与肥胖和糖尿病的关系.方法 分别测定单纯性肥胖组(30例)、糖尿病组(30例)和正常对照组(20例)的体重指数(BMI)、腰围、臀围、空腹胰岛素(FINS)、空腹血糖(FBS)、血脂、腹脂素、瘦素和脂联素的水平,计算胰岛素抵抗指数(HOMA-IR).结果 (1)单纯性肥胖组和糖尿病组血清腹脂素及瘦素水平高于正常对照组,而脂联素水平明显降低 (P＜0.05);(2)糖尿病组血清腹脂素、瘦素及脂联素水平与单纯肥胖组比较差异无显著性(P=0.450);(3)腹脂素与BMI、腰围、腰臀比、瘦素呈正相关,与脂联素呈负相关;(4)腰围可较好地预测腹脂素水平.结论 腹脂素及瘦素在单纯性肥胖和糖尿病患者中明显升高,而脂联素降低,其表达水平与肥胖程度及肥胖类型(中心性肥胖)密切相关.     

Alpha-lipoic acid effect on leptin and adiponectin concentrations: a systematic review and meta-analysis of randomized controlled trials

New evidence suggests that dysregulation of adipocytokines caused by excess adiposity plays an important role in the pathogenesis of various obesity comorbidities. Our aim in this meta-analysis was to determine the effect of alpha-lipoic acid (ALA) supplementation on serum levels of leptin and adiponectin. We searched Scopus, PubMed, Google Scholar, and ISI Web of Science from inception up to July 2019. Mean difference for leptin and adiponectin were calculated by subtracting the change from baseline in each study group. Summary estimates for the overall effect of ALA on serum leptin and adiponectin concentrations were calculated using random effects model. Results were presented as weighted mean difference (WMD) and their 95% confidence intervals (CI). Between-study heterogeneity was examined using the I2 statistics. Eight studies were included in systematic review and seven studies in meta-analysis. The overall effect suggested a significant decrement in serum leptin concentrations (WMD = − 3.63; 95% CI, − 5.63, − 1.64 μg/ml; I2 = 80.7%) and a significant increase in serum levels of adiponectin (WMD = 1.98 μg/ml; 95% CI, 0.92, 3.04; I2 = 95.7%). Subgroup analyses based on age showed a significant reduction in leptin levels only in younger adults, and subgroup analysis based on duration indicated in studies with a duration of more than 8 weeks adiponectin levels increased significantly and leptin levels decreased significantly. Our results revealed ALA decreased leptin and increased adiponectin especially in studies lasted more than 8 weeks. We still need more studies with different ALA dose, intervention duration, and separately on male and female.     

Obesity and metabolic syndrome: long-term benefits of central leptin gene therapy

The recent rapid rise in the incidence of obesity has prompted investigations into understanding the hormonal and neuronal pathways involved in body weight homeostasis in order to devise novel therapeutic strategies. The early enthusiasm for the adipocyte hormone leptin as a regulator of fat mass was largely discarded because of the apparent development of leptin resistance, as seen in obese subjects with elevated blood leptin levels. We postulated that this leptin ineffectiveness may be caused by a lack of leptin availability at target sites in the hypothalamus. To test this hypothesis, we used viral vectors to introduce the leptin gene into the brain for a sustained supply of leptin in the hypothalamus. A single injection of recombinant adeno-associated virus encoding the leptin gene (rAAV-lep) into the third cerebroventricle prevented the aging-associated gradual increase in body weight and adiposity in adult rats for 6 months of the experiment. When administered to prepubertal rats, significantly lower body weight gain and adiposity were maintained for up to 10 months of the experiment. In addition, obesity was prevented in rats introduced to a high-fat diet and also reversed in obese-prone rats maintained on a high-fat diet. Body weight homeostasis and loss of adiposity by leptin gene therapy was achieved by an increase in energy expenditure, and when the rAAV-lep titer was increased, there was also a voluntary reduction in food intake. Importantly, this therapy reduced blood levels of insulin, triglycerides and free fatty acids, the pathophysiologic correlates of the metabolic syndrome. Thus, the long-term beneficial effects of central leptin gene therapy may herald the development of newer therapeutic strategies to control the epidemic of obesity and related metabolic disorders.     

Effects of Piper nigrum extracts: Restorative perspectives of high-fat diet-induced changes on lipid profile,body composition,and hormones in Sprague–Dawley rats

Abstract

Context: Piper nigrum Linn (Piperaceae) (PnL) is used in traditional medicine to treat gastric ailments, dyslipidemia, diabetes, and hypertension.

Objective: The present study explores the possible protective effects of P. nigrum extracts on high-fat diet-induced obesity in rats.

Materials and methods: High-fat diet-induced obese rats were treated orally with 200?mg/kg bw of different extracts (hexane, ethylacetate, ethanol, and aqueous extracts) of PnL for 42?d. The effects of PnL extracts on body composition, insulin resistance, biochemical parameters, leptin, adiponectin, lipid profile, liver marker enzymes, and antioxidants were studied.

Results and discussion: The HFD control group rats showed a substantial raise in body weight (472.8?±?9.3?g), fat% (20.8?±?0.6%), and fat-free mass (165.9?±?2.4?g) when compared with normal control rats whose body weight, fat%, and fat-free mass were 314.3?±?4.4?g, 6.4?±?1.4%, and 133.8?±?2.2?g, respectively. Oral administration of ethyl acetate or aqueous extracts of PnL markedly reduced the body weight, fat%, and fat-free mass of HFD-fed rats. In contrast to the normal control group, a profound increase in plasma glucose, insulin resistance, lipid profile, leptin, thiobarbituric acid reactive substance (TBARS), and the activities of lipase and liver marker enzymes, and a decrease in adiponectin and antioxidant enzymes were noted in HFD control rats. Administration of PnL extracts to HFD-induced obese rats significantly (p?<?0.05) restored the above profiles.

Conclusion: PnL extracts significantly reduced the body weight, fat%, and ameliorated HFD-induced hyperlipidemia and its constituents.     

Monoterpene phenolic compound thymol prevents high fat diet induced obesity in murine model

Context: Obesity has become a worldwide health problem. Most of the synthetic anti-obesity drugs have failed to manage the obesity due to either ineffectiveness or adverse effect. The research of prominent chemical constituents from herbal for the management of obesity has greatly increased.

Objective: The main objective of the present study was intended to examine the effects of thymol in high-fat diet (HFD)-induced obesity in murine model.

Methods: Male Wistar rats were fed HFD for 6 weeks to induce obesity. Thymol (14?mg/kg) administered orally twice a day to HFD-fed rats for 4 weeks. Alteration in body weight gain, visceral fat-pads weight and serum biochemical markers were assessed.

Results: At the end of study, rats fed with HFD exhibited significantly (p?p?Discussion and conclusions: Thymol prevents HFD-induced obesity in murine model through several mechanisms including attenuation of visceral fat accumulation, lipid lowering action, improvement of insulin and leptin sensitivity and enhanced antioxidant potential.     

A parametric analysis of olanzapine-induced weight gain in female rats

RATIONALE: Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear. OBJECTIVE: The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings. METHODS: Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration. RESULTS: Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg). CONCLUSIONS: These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.     

Protective effect of benidipine against the development of glomerular sclerosis in experimental nephrotic syndrome.

An experimental focal segmental glomerular sclerosis (FSGS) was induced by the combined administration of puromycin aminonucleoside (PAN) and protamine sulfate (PS). Blood collections were made on days 0, 37, 70 and 94. Urine collections were made on days 0, 24, 80 and 94. Vehicle-treated rats showed severe proteinuria and an increase in serum total cholesterol (sTC). Benidipine (1 or 3 mg/kg, p.o.)-treated rats exhibited less proteinuria and lower sTC than the vehicle-treated rats. On days 70 and 94, both blood urea nitrogen (BUN) and serum creatinine (sCR) values in the vehicle-treated rats were significantly higher than those in normal rats (without treatment with PAN and PS). On the other hand, the treatment with benidipine (1 or 3 mg/kg, p.o.) attenuated the increases in BUN and sCR. On day 94, vehicle-treated rats showed a significant decrease in creatinine clearance as compared with normal rats, but benidipine (1 or 3 mg/kg, p.o.)-treated rats did not. The histology was examined on day 94. Vehicle-treated rats demonstrated a significantly greater percentage of glomeruli with segmental areas of glomerulosclerosis/hyalinosis, mesangial cell proliferation, and mesangial foam cell. Benidipine (3 mg/kg, p.o.) ameliorated the development of renal regeneration as estimated by histological examination. These results suggest that the Ca-channel blocker benidipine is a favorable drug for preventing the progression of glomerular sclerosis.     

西格列汀对肥胖大鼠代谢指标及脂肪因子chemerin脂联素水平的影响

目的 研究西格列汀对肥胖大鼠代谢指标及脂肪因子chemerin、脂联素(ADPN)水平的影响及其可能机制,并探讨chemerin及ADPN与肥胖的关系。方法 将30只大鼠随机分为正常对照组(NC组)、肥胖对照组(HF组)和肥胖西格列汀干预组(SP组),ELISA法分别测定干预前后各组大鼠生化指标,Western blot 法检测大鼠脂肪、肝脏、肌肉及肾脏组织chemerin及ADPN蛋白表达水平。结果 与NC组相比,HF组大鼠血清chemerin、体质量(BW),空腹血糖(FBG)、胰岛素(FINS)、总胆固醇(TG)、甘油三酯(TC)、低密度脂蛋白胆固醇(LDL-C),胰岛素抵抗指数(HOMO-IR)增高,血清ADPN及高密度脂蛋白胆固醇(HDL-C)降低(P<0.05),HF组大鼠脂肪、肝脏、肌肉及肾脏组织的chemerin蛋白表达量较NC组对应组织的表达量增加(P<0.05),脂肪、肝脏及肌肉组织的ADPN表达量减少(P<0.05)。与HF组相比,SP组大鼠FBG、FINS、TC、TG、LDL-C、HOMO-IR、血清chemerin水平降低, HDL-C及血清ADPN水平升高(P<0.05),脂肪、肝脏、肾脏及肌肉组织的chemerin蛋白表达量减少,脂肪、肌肉组织的ADPN表达增加(P<0.05)。干预前chemerin、ADPN与BW、FBG、TG、HDL-C、LDL-C、FINS、HOMO-IR有相关性,干预后chemerin、ADPN与BW、LDL-C、FINS、HOMO-IR有相关性,ADPN与HDL-C呈正相关。结论 chemerin及ADPN参与糖脂代谢过程,西格列汀可改善血清学各代谢指标,并通过影响chemerin及ADPN来改善肥胖大鼠胰岛素敏感性。     

Discovery of a Potent 9‐Deazaxanthine‐based Agent for the Treatment of Obesity‐Related Non‐alcoholic Fatty Liver Disease

A series of deazaxanthine‐based derivatives were rationally prepared and evaluated. 8g exhibited the most potent glucose‐lowering effect on HepG2 cell line and modulated adiponectin and leptin expression in 3T3‐L1 adipocytes. Oral administration of 8g at 25 mg/kg/day for 4 weeks manifested therapeutic effects on high‐fat diet‐induced non‐alcoholic fatty liver disease (NAFLD) by decreasing the weights of the body, liver, and fat. 8g also modulated the serum levels of fasting glucose and adiponectin, triglycerides, low‐density lipoprotein‐cholesterol, and alanine aminotransferase, as well as the hepatic concentrations of triglycerides, total cholesterol. Moreover, 8g significantly decreased steatosis and blocked the increase of adipocytes and the size of adipose tissues from NAFLD. In the DIO mice model, 8g ameliorated the obesity‐related symptoms and normalized serum biomarkers.     

Rimonabant: new drug. Obesity: loss of a few kilos, many questions

(1) The treatment of obesity is based on calorie reduction and moderate physical activity. (2) Rimonabant, a CB1 cannabinoid receptor antagonist, is marketed in Europe for the adjuvant treatment of obesity, in combination with a low-calorie diet and physical exercise. (3) Four double-blind placebo-controlled trials involving about 6500 patients show that, when combined with a low-calorie diet, rimonabant 20 mg/day leads to an average weight loss of 4 or 5 kg more than placebo after one year of treatment. This is similar to the weight loss reported with orlistat (indirect comparison). Effects on the lipid profile are similar to those reported with sibutramine. (4) Rimonabant has not been shown to reduce morbidity or mortality. Patients regain the weight they lost within about 9 months after rimonabant withdrawal. (5) Three placebo-controlled trials have evaluated rimonabant in smoking cessation. The available results (a single conference abstract) are inconclusive. In early 2006 the FDA and the European Medicines Agency refused to approve rimonabant for this use. (6) Adverse effects mentioned in published clinical trials of rimonabant include mental disorders (anxiety, depression), neurological disorders (dizziness) and gastrointestinal disorders (nausea, diarrhoea). No postmarketing safety data are available. The possible long-term adverse effects of rimonabant are unknown. (7) In practice, when drug therapy is considered for weight loss, it seems unwise to prescribe rimonabant: this new drug has only limited symptomatic effects and its adverse effects, especially in the long term, are poorly documented.     

Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro)

Background and purpose:

We have previously shown that treatment with zinc plus cyclo-(His-Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) rats and in aged obese Sprague-Dawley (S-D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G-K rats and non-diabetic, obese S-D rats.

Experimental approach:

G-K rats aged 1.5–10 months and non-diabetic overweight or obese S-D rats aged 6–18 months were treated with 0–6 mg CHP plus 0–10 mg zinc·L⁻¹ drinking water for 2–4 weeks, and changes in weight, serum leptin and adiponectin levels, food and water intakes were measured.

Key results:

The optimal dose of CHP (in combination with zinc) to reduce weight and plasma leptin levels and to increase plasma adiponectin levels was close to 0.1 mg·kg⁻¹·day⁻¹, in either mature G-K rats and aged overweight or obese S-D rats. Food and water intake significantly decreased in ZC treated rats in both aged S-D rats and mature G-K rats, but not in young S-D and G-K rats.

Conclusions and implications:

ZC treatment improved weight control and may be a possible treatment for overweight and obesity.     

The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes

Adipocyte cell proliferation is an important process in body fat mass development in obesity. Adiponectin or Acrp30 is an adipocytokine exclusively expressed and secreted by adipose tissue that regulates lipid and glucose metabolism and plays a key role in body weight regulation and homeostasis. Adiponectin mRNA expression in adipose tissue and plasma level of adiponectin are decreased in obesity and type 2 diabetes. In obese rodents, the selective CB(1) receptor antagonist rimonabant reduces food intake and body weight and improves lipid and glucose parameters. We have reported previously that rimonabant stimulated adiponectin mRNA expression in adipose tissue of obese fa/fa rats, by a direct effect on adipocytes. We report here that rimonabant (10-400 nM) inhibits cell proliferation of cultured mouse 3T3 F442A preadipocytes in a concentration-dependent manner. In parallel to this inhibitory effect on preadipocyte cell proliferation, rimonabant (25-100 nM) stimulates mRNA expression and protein levels of two late markers of adipocyte differentiation (adiponectin and glyceraldehyde-3-phosphate dehydrogenase) with a maximal effect at 100 nM, without inducing the accumulation of lipid droplets. Furthermore, treatment of mouse 3T3 F442A preadipocytes with rimonabant (100 nM) inhibits basal and serum-induced p42/44 mitogen-activated protein (MAP) kinase activity. These results suggest that inhibition of MAP kinase activity by rimonabant may be one of mechanisms involved in the inhibition of 3T3 F442A preadipocyte cell proliferation and stimulation of adiponectin and GAPDH expression. The inhibition of preadipocyte cell proliferation and the induction of adipocyte late "maturation" may participate in rimonabant-induced antiobesity effects, particularly the reduction of body fat mass.     

肥胖大鼠非酒精性脂肪肝与血清脂联素和肿瘤坏死因子α的关系及吡格列酮干预

目的观察营养性肥胖大鼠非酒精性脂肪肝(NAFLD)与血清脂联素和肿瘤坏死因子α(TNF-α)的关系,以及吡格列酮干预后的变化。方法45只SD♂大鼠随机分为3组:吡格列酮组(P)、高脂对照组(HF)和普通饮食组(NC),各15只。P、HF组给予高脂饮食,NC组给予普通饲料;12wk后,P组行吡格列酮10mg·kg-1.d-1灌胃,HF组和NC组用相应溶剂灌胃,均灌胃4wk。检测血清脂联素、TNF-α、游离脂肪酸(FFA)水平和其他生化指标等,计算Lee′s指数、HOMA-IR指数和肝脏指数,行肝脏病理切片和HE染色。结果与NC组相比,HF组大鼠体重、肝脏指数、FPG、FINS、ALT、HOMA-IR和血清TNF-α水平均明显增高,血清脂联素水平降低(P<0.05),肝细胞出现脂肪变性。与HF组比较,P组大鼠肝脏指数、HOMA-IR、FFA、TNF-α均降低,脂联素水平升高(P<0.05),肝细胞脂肪变性明显改善。HF组大鼠血清FFA、TNF-α与HOMA-IR、肝脏指数正相关,脂联素与之负相关(P<0.05)。结论高脂饮食可引起大鼠营养性肥胖、胰岛素抵抗和NAFLD;吡格列酮能提高胰岛素敏感性,改善脂肪细胞变性,可能与降低TNF-α、升高脂联素有关。     

The effects of physiological and pharmacological weight loss on adiponectin and leptin mRNA levels in the rat epididymal adipose tissue

In subjects with obesity, diabetes and coronary artery disease, circulating levels of leptin increased while that of adiponectin is decreased. In this study we have investigated effects of physiological and pharmacological weight reduction on leptin and adiponectin mRNA expression. Wistar rats were fed either standard laboratory chow for 16 weeks (chow-fed) or given a fat-enriched, glucose-enriched diet (diet-fed) for 8 weeks. After 8 weeks, diet-fed group was subdivided into three subgroups, namely, an untreated obese, or were returned to chow diet, or treated with fenofibrate for further 8 week. After 16 weeks, compared with chow-fed group, diet-fed rats had significantly higher body weight, epididymal fat pad mass, and plasma levels of insulin, leptin, adiponectin, non-esterified fatty acids and triglycerides (P<0.001, for all). Moreover, untreated obese rats had significantly (P<0.01, for both) raised levels of Ob mRNA but reduced adiponectin mRNA levels in epididymal fat pads compared with chow-fed group. These changes were corrected by chronic removal of the high-energy diet and fenofibrate treatment. These findings indicate that physiological or pharmacological lowering of body weight together with circulating plasma lipids play a significant role in leptin and adiponectin synthesis and metabolism.