Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding

Background and purpose:

Endocannabinoids in tissues controlling energy homeostasis are altered in obesity, thus contributing to metabolic disorders. Here we evaluate endocannabinoid dysregulation in the small intestine of mice with diet-induced obesity (DIO) and in peripheral tissues of Zucker and lean rats following food deprivation and re-feeding.

Experimental approach:

Intestinal transit, evaluated using rhodamine-B-labelled dextran, and small intestinal endocannabinoid levels, measured by liquid chromatography mass spectrometry, were measured in mice fed normal or high-fat diets (HFDs). Endocannabinoid levels were measured also in various tissues of lean and Zucker rats fed ad libitum or following overnight food deprivation with and without subsequent re-feeding.

Key results:

After 8 weeks of HFD, baseline intestinal transit was increased in DIO mice and enhanced by cannabinoid CB₁ receptor antagonism less efficaciously than in lean mice. Small intestinal anandamide and 2-arachidonoylglycerol levels were reduced and increased respectively. In Zucker rats, endocannabinoids levels were higher in the pancreas, liver and duodenum, and lower in the subcutaneous adipose tissue. Food deprivation increased endocannabinoid levels in the duodenum and liver of both rat strains, in the pancreas of lean rats and in adipose tissues of Zucker rats.

Conclusions and implications:

Reduced anandamide levels might account for increased intestinal motility in DIO mice. Regulation of endocannabinoid levels in rat peripheral tissues, induced by food deprivation and re-feeding, might participate in food intake and energy processing and was altered in Zucker rats. These data, together with previous observations, provide further evidence for dysregulation of peripheral endocannabinoids in obesity.     

Aliskiren reduces body-weight gain,adiposity and plasma leptin during diet-induced obesity

Background and purpose:

Overfeeding increases adipose tissue mass and leptin production and up-regulates the renin-angiotensin system in adipose tissue in rodents. Here, we determined the effect of chronic treatment with the renin inhibitor, aliskiren, in a model of diet-induced obesity in mice, on: (i) body weight, adipose tissue weight and plasma leptin; (ii) food intake and caloric efficiency; and (iii) angiotensin II (Ang II) in adipose tissue.

Experimental approach:

Four-week-old C57BL/6J mice (n= 40) received aliskiren (50 mg·kg⁻¹·day⁻¹; 6 weeks) by means of a subcutaneous osmotic Alzet minipump. Animals were given either a low-fat (10% kcal from fat) or a high-fat diet (45% kcal from fat) during this period. Food-intake and body-weight variation were monitored during treatment.

Key results:

In addition to a decrease of plasma renin activity, aliskiren reduced body-weight gain, adipose pads and plasma leptin concentration, independent of the diet. In adipose tissue, local concentrations of Ang II were also reduced by aliskiren.

Conclusions and implications:

Aliskiren limited the gain of adiposity in young mice. This effect was not due to changes in food intake or caloric efficiency and might be related to a down-regulation of the local renin-angiotensin system in adipose tissue. These effects were accompanied by reduced plasma leptin levels. As Ang II favours differentiation of adipocytes, it is possible that the decreased adipose tissue was linked to changes in adipocyte size and number.     

Mechanism of the anti-obesity effects induced by a novel Melanin-concentrating hormone 1-receptor antagonist in mice

Background and purpose:

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists.

Experimental approach:

To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions.

Key results:

Treatment with the MCH1 receptor antagonist at 30 mg·kg⁻¹ for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis.

Conclusions and implications:

Our results indicate that an MCH1 receptor antagonist caused anti-obesity effects im mice by acting on both energy intake and energy expenditure.     

Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats

BACKGROUND AND PURPOSE

Peripheral blockade of cannabinoid CB₁ receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting CB₁ receptor antagonists. In this study we analysed the effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist with poor brain penetration, in an animal model of diet-induced obesity.

EXPERIMENTAL APPROACH

To induce obesity, male Wistar rats were fed a high-fat diet (HFD; 60 kcal% fat) whereas controls received a standard diet (SD; 10 kcal% fat). Following 10 weeks of feeding, animals received a daily i.p. injection of vehicle or 3 mg·kg⁻¹ LH-21 for 10 days. Plasma and liver samples were used for biochemical analyses whereas visceral fat-pad samples were analysed for lipid metabolism gene expression using real-time RT-PCR. In addition, the potential of LH-21 to interact with hepatic cytochrome P450 isoforms and cardiac human Ether-à-go-go Related Gene (hERG) channels was evaluated.

KEY RESULTS

LH-21 reduced feeding and body weight gain in HFD-fed animals compared with the control group fed SD. In adipose tissue, this effect was associated with decreased gene expression of: (i) leptin; (ii) lipogenic enzymes, including SCD-1; (iii) CB₁ receptors; and (iv) both PPARα and PPARγ. Although there were no significant differences in plasma parameters between HFD- and SD-fed rats, LH-21 did not seem to induce hepatic, cardiac or renal toxicity.

CONCLUSIONS AND IMPLICATIONS

These results support the hypothesis that treatment with the peripherally neutral acting CB₁ receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue.     

Insulin therapy stimulates lipid synthesis and improves endocrine functions of adipocytes in dietary obese C57BL/6 mice

Aim:

To evaluate whether insulin intervention could affect the metabolic and endocrine functions of adipose tissue.

Methods:

C57BL/6 mice were fed on a high-fat-diet for 12−16 weeks to induce insulin resistance. Insulin intervention was administered in the high-fat-diet mice for 4 weeks at 12 weeks (early insulin treatment) or 16 weeks (late insulin treatment). Intraperitoneal glucose tolerance tests were performed before and after insulin treatment. Expression levels of factors involved in the triglyceride synthesis and endocrine functions of adipose tissue including phosphoenolpyruvate carboxykinase (PEPCK-C), fatty acid synthase (FAS), aquaporin 7 (AQP7), adiponectin, visfatin, and interleukin-6 (IL-6) were determined by Western blot.

Results:

In the obese mice, glucose tolerance was impaired; triglyceride content was increased in the liver tissue; protein expression of FAS and adiponectin was decreased; expression of visfatin was increased in adipose tissue. After 4-week insulin treatment, glucose tolerance was improved; triglyceride content was decreased in the liver and skeletal muscle; expression of PEPCK-C, FAS, and adiponectin was increased in the adipose tissue; IL-6 and AQP7 expression was reduced in the fat. Early insulin treatment had better effect in increasing the expression of FAS and PEPCK-C and decreasing the expression of IL-6.

Conclusion:

These results indicate that insulin can target adipocytes for improvement of insulin sensitivity through stimulating triglyceride synthesis and partly improving endocrine functions.     

Effects of liraglutide and sibutramine on food intake,palatability, body weight and glucose tolerance in the gubra DIO-rats

Aim:

To validate the gubra DIO-rats as a useful animal model of human obesity.

Methods:

The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d.

Results:

Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion.

Conclusion:

This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference.     

The phospholipase A2 inhibitor methyl indoxam suppresses diet-induced obesity and glucose intolerance in mice

Background and purpose:

Previous results have shown that mice lacking in the group 1B phospholipase A₂ (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high-fat/high-carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet-induced obesity and diabetes.

Experimental approach:

Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared.

Key results:

Wild-type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg·kg⁻¹ of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet-induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b-mediated postprandial lysophospholipid absorption.

Conclusions and implications:

These results show that oral supplementation of a diabetogenic diet with the Pla2g1b inhibitor methyl indoxam effectively suppresses diet-induced obesity and diabetes in mice. This suggests that Pla2g1b inhibition may be a potentially effective oral therapeutic option for treatment of obesity and diabetes.     

Quantitative efficacy of soy isoflavones on menopausal hot flashes

AIM

This study aimed to quantitate the efficacy of soy isoflavones in the treatment of menopausal hot flashes.

METHODS

Model based meta-analysis (MBMA) was used to quantitate the efficacy of soy isoflavones. We conducted a systemic literature search to build a time–effect model for placebo and soy isoflavones in treating menopausal hot flashes. Studies were identified, subjected to inclusion and exclusion criteria, and reviewed.

RESULTS

From 55 articles, 16 studies of soy isoflavones met the inclusion criteria, and contained 65 and 66 mean effect values in placebo and soy isoflavone groups, respectively, from about 1710 subjects. Interestingly, the developed model was found to describe adequately the time course of hot flashes reduction after administration of placebo and soy isoflavones. Using this model, we found that the maximal percentage change of hot flashes reduction by soy isoflavones was 25.2% after elimination of the placebo effect, accounting for 57% of the maximum effects of estradiol (E_{max-estradiol} = 44.9%). However, a time interval of 13.4 weeks was needed for soy isoflavones to achieve half of its maximal effects, much longer than estradiol, which only required 3.09 weeks. These results suggest that treatment intervals of 12 weeks are too short for soy isoflavones, which require at least 48 weeks to achieve 80% of their maximum effects.

CONCLUSIONS

Soy isoflavones show slight and slow effects in attenuating menopausal hot flashes compared with estradiol.     

Retinol-binding protein 4 : a possible role in cardiovascular complications

BACKGROUND AND PURPOSE

Retinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition.

EXPERIMENTAL APPROACH

Adipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice.

KEY RESULTS

Mice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-α and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1.

CONCLUSION AND IMPLICATIONS

Our results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines.     

Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis

BACKGROUND AND PURPOSE

Treatment with thiazolidinediones, insulin-sensitizing drugs, enhances adipogenesis, which may result in unwanted increase in adiposity. Based on the suggested metabolic effects of oxytocin, the aims of the present study were to: (i) determine whether chronic treatment with oxytocin exerts positive effects on white adipose tissue growth without increasing adiposity; (ii) investigate possible mechanisms of action of oxytocin by measuring the level of gene expression of adipogenic factors; and (iii) test the hypothesis that oxytocin''s effect on adipose tissue involves specific activation of eukaryotic elongation factor 2 (eEF2).

EXPERIMENTAL APPROACH

Adult rats were subcutaneously treated with oxytocin (3.6 µg·100 g⁻¹ body weight day⁻¹) via osmotic minipumps for 2 weeks. Adipocytes from epididymal adipose tissue were isolated and their size evaluated by light microscopy. Gene expression of adipogenic and angiogenic factors was determined by real-time PCR and dephosphorylation of eEF2 by immunoblotting.

KEY RESULTS

Oxytocin treatment decreased the diameter of adipocytes and increased the epididymal adipose tissue protein content without changing the adipose tissue mass. Increases in fatty acid binding protein, peroxisome proliferator-activated receptor γ, insulin-sensitive glucose transporter 4, leptin and CD31 mRNA levels were noted in the epididymal and/or retroperitoneal fat tissue of oxytocin-treated rats. Oxytocin enhanced the dephosphorylation of eEF2 in the epididymal adipose tissue.

CONCLUSIONS AND IMPLICATIONS

The present results demonstrate that subchronic treatment with oxytocin induces adipogenic and angiogenic effects and that the eEF2 signalling pathway is involved in these effects of oxytocin on adipose tissue in vivo. These findings are likely to motivate further research and indicate new approaches for modulating adipose tissue morphology and metabolism.     

Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids

Aim:

Stromelysin 1 (matrix metalloproteinase 3; MMP-3) is an enzyme known to be involved in tumor invasion and metastasis. In this study, flavonoids from vegetables and fruits, such as quercetin, kaempferol, genistein, genistin, and daidzein, were tested for their ability to modulate the secretion and activity of MMP-3 in the MDA-MB-231 breast cancer cell line. In addition, we investigated the in vitro effects of flavonoids on MDA-MB-231 cell invasion.

Methods:

The toxic concentration range of flavonoids was evaluated using the MTT assay. The ability of MDA-MB-231 cells to invade was evaluated using a modified Boyden chamber system. The activity of MMP-3 was determined by casein zymography. The secretion of MMP-3 was evaluated using Western blotting, casein zymography and confirmed by ELISA.

Results:

Some putative flavonoids, ie, quercetin and kaempferol (flavonols), significantly inhibited the in vitro invasion of MDA-MB-231 cells in a concentration-dependent manner, with IC₅₀ values of 27 and 30 μmol/L, respectively. Quercetin and kaempferol also reduced MMP-3 activity in a dose-dependent manner, with IC₅₀ values in the range of 30 μmol/L and 45 μmol/L, respectively. None of the flavonoids had a significant effect on the secretion of MMP-3.

Conclusion:

These data show that the flavonols quercetin and kaempferol have higher anti-invasion potency and higher MMP-3 inhibitory activity than isoflavones genistein, genistin and daidzein. In contrast, neither flavonols nor isoflavones have any effect on MMP-3 secretion.     

Obesity enhances eosinophilic inflammation in a murine model of allergic asthma

Background and purpose:

Obesity is associated with deterioration in asthma outcomes. Although airways eosinophil accumulation is characteristic of lung allergic diseases, little is known about the influence of obesity on the allergic eosinophil trafficking from bone marrow to lung tissues, and recruitment to airways lumen. Here, we have assessed the effects of diet-induced obesity on allergic eosinophilic inflammation in mice, examining eosinophil trafficking from bone marrow to airways, and production of T_H1/T_H2 cytokines.

Experimental approach:

C57BL/6 mice fed for 10 weeks with standard chow or high-fat diet were sensitized and challenged with ovalbumin. At 24–96 h post-ovalbumin challenge, bronchoalveolar lavage (BAL) fluid, lung tissue and bone marrow were examined.

Key results:

The high-fat-fed mice exhibited increased body weight and epididymal fat, glucose intolerance and alterations in lipid profile compared with the lean mice. Obesity markedly elevated serum leptin and lowered adiponectin levels. Ovalbumin challenge in obese mice promoted a markedly higher eosinophil accumulation in bone marrow and connective tissue surrounding the bronchial and bronchiolar segments. Eosinophil number in BAL fluid of obese mice was lower at 24 and 48 h. Levels of interleukin (IL)-5, eotaxin, tumour necrosis factor-α and IL-10 in BAL fluid of obese mice were significantly higher than in lean mice.

Conclusions and implications:

Diet-induced obesity enhanced eosinophil trafficking from bone marrow to lung tissues, and delayed their transit through the airway epithelium into the airway lumen. Consequently, eosinophils remain longer in lung peribronchiolar segments due to overproduction of T_H1/T_H2 cytokines and chemokines.     

Atorvastatin improves insulin sensitivity in mice with obesity induced by monosodium glutamate

Aim:

To examine the mechanisms underlying the effects of atorvastatin on glucose and lipid metabolism.

Methods:

Mice with insulin resistance and obesity induced by monosodium glutamate (MSG) were used. Atorvastatin (80 mg·kg⁻¹·d⁻¹) or vehicle control treatment was given orally once a day for 30 days. Plasma levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and free fatty acids were monitored. Serum insulin and glucose concentrations were used to calculate the insulin resistance index and insulin sensitivity index using a homeostasis model. Body length, waistline circumference, intraperitoneal adipose tissue mass, and total body mass were measured. Semi-quantitative RT-PCR and Western analysis were used to determine the expression of inflammatory factors and proteins involved in inflammation signaling pathways.

Results:

Atorvastatin improved insulin sensitivity, ameliorated glucose tolerance, and decreased plasma levels of total cholesterol, triglycerides, LDL-C, HDL-C and free fatty acids. Semi-quantitative RT-PCR and Western analysis revealed increased expression of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in serum and adipose tissue in MSG obese mice. Atorvastatin treatment decreased expression of IL-6, TNF-α, nuclear factor κB (NF-κB) and I-kappa-B (IκB) kinase-β, but increased the expression of IκB, in adipose tissue.

Conclusion:

Atorvastatin is a potential candidate for the prevention and therapy of diseases associated with insulin resistance such as type 2 diabetes mellitus and cardiovascular disease. One possible mechanism underlying the effects of atorvastatin on glucose and lipid metabolism may be to ameliorate a state of chronic inflammation.     

Effect of Argyreia speciosa root extract on cafeteria diet-induced obesity in rats

Objectives:

To evaluate the antiobesity effects of the ethanolic extract of Argyreia speciosa roots in rats fed with a cafeteria diet (CD).

Materials and Methods:

Obesity was induced in albino rats by feeding them a CD daily for 42 days, in addition to a normal diet. Body weight and food intake was measured initially and then every week thereafter. On day 42, the serum biochemical parameters were estimated and the animals were sacrificed with an overdose of ether. The, liver and parametrial adipose tissues were removed and weighed immediately. The liver triglyceride content was estimated. The influence of the extract on the pancreatic lipase activity was also determined by measuring the rate of release of oleic acid from triolein.

Results:

The body weight at two-to-six weeks and the final parametrial adipose tissue weights were significantly lowered (P < 0.01 and P < 0.05, respectively) in rats fed with the CD with Argyreia speciosa extract 500 mg/kg/day as compared to the CD alone. The extract also significantly reduced (P < 0.01) the serum contents of leptin, total cholesterol, low density lipoprotein (LDL), and triglycerides, which were elevated in rats fed with CD alone. In addition, the extract inhibited the induction of fatty liver with the accumulation of hepatic triglycerides. The extract also showed inhibition of pancreatic lipase activity by using triolein as a substrate.

Conclusions:

The ethanolic extract of Argyreia speciosa roots produces inhibitory effects on cafeteria diet-induced obesity in rats.     

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

Aim:

Wogonin (5,7-dihydroxy-8-methoxyflavone), a major bioactive compound of the flavonoid family, is commonly extracted from the traditional Chinese medicine Scutellaria baicalensis and possesses antioxidant and anti-inflammatory activities and is assumed to have anti-diabetes function. Indeed, a current study has shown that it can possibly treat metabolic disorders such as those found in db/db mice. However, the underlying molecular mechanism remains largely unclear. The aim of this study was to investigate the impact of wogonin on osteopontin (OPN) expression in adipose tissue from type 1 diabetic mice and in 3T3-L1 adipocytes.

Methods:

Type 1 diabetes was induced by streptozotocin (STZ) injection. 3T3-L1 preadipocytes were converted to 3T3-L1 adipocytes through treatment with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IBMX). Western blot analysis and RT-PCR were performed to detect protein expression and mRNA levels, respectively.

Results:

Wogonin treatment suppressed the increase in serum OPN levels and reduced OPN expression in adipose tissue from STZ-induced type 1 diabetic mice. Administration of wogonin enhanced PPARα expression and activity. Silencing of PPARα diminished the inhibitory effects of wogonin on OPN expression in 3T3-L1 adipocytes. Furthermore, the levels of c-Fos and phosphorylated c-Jun were reduced in wogonin-treated adipose tissue and 3T3-L1 adipocytes. In addition, wogonin treatment dramatically mitigated p38 MAPK phosphorylation. Pharmacological inhibition of p38 MAPK by its specific inhibitor SB203580 increased PPARα activity and decreased OPN expression.

Conclusion:

Our results suggest that wogonin downregulated OPN expression in adipocytes through the inhibition of p38 MAPK and the sequential activation of the PPARα pathway. Given the adverse effects of high OPN levels on metabolism, our results provide evidence for the potential administration of wogonin as a treatment for diabetes.     

Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight gain, hyperlipidemia, and hepatic steatosis in db/db mice

Aim:

To test whether pharmacological inhibition of Diacylglycerol acyltransferase 1 (DGAT1) by a small-molecule inhibitor H128 can improve metabolism disorders in leptin receptor-deficient db/db mice.

Methods:

To investigate the effect of H128 on intestinal fat absorption,db/db mice were acutely given a bolus of corn oil by gavage. The mice were further orally administered H128 (3 and 10 mg/kg) for 5 weeks. Blood glucose, lipids, insulin, ALT, and AST as well as hepatic triglycerides were measured. The insulin tolerance test was performed to evaluate insulin sensitivity. The expression of genes involved in fatty acid oxidation was detected by RT-PCR.

Results:

Oral administration of H128 (10 mg/kg) acutely inhibited intestinal fat absorption following a lipid challenge in db/db mice. Chronic treatment with H128 significantly inhibited body weight gain, decreased food intake, and induced a pronounced reduction of serum triglycerides. In addition, H128 treatment markedly ameliorated hepatic steatosis, characterized by decreased liver weight, lipid droplets, and triglyceride content as well as serum ALT and AST levels. Furthermore, H128 treatment increased the expression of the CPT1 and PPARα genes in liver, suggesting that H128 enhanced fatty acid oxidation in db/db mice. However, neither blood glucose nor insulin tolerance was affected by H128 treatment throughout the 5-week experimental period.

Conclusion:

DGAT1 may be an effective therapeutic target for the treatment of obesity, hyperlipidemia and hepatic steatosis.     

Irbesartan treatment up-regulates hepatic expression of PPAR�� and its target genes in obese Koletsky (fak/fak) rats: a link to amelioration of hypertriglyceridaemia

BACKGROUND AND PURPOSE

Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT₁) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear.

EXPERIMENTAL APPROACH

Male obese Koletsky (fa^k/fa^k) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg·kg⁻¹·day⁻¹) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting.

KEY RESULTS

In Koletsky (fa^k/fa^k) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)α and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARα expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARγ and its downstream genes or hepatic genes that mediate fatty acid synthesis.

CONCLUSIONS AND IMPLICATIONS

These findings demonstrate that irbesartan treatment up-regulates PPARα and several target genes in liver of obese spontaneously hypertensive Koletsky (fa^k/fa^k) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan.     

The effect of inhibition of endoplasmic reticulum stress on lipolysis in white adipose tissue in a rat model of chronic kidney disease

Aim; Lipolysis in fat tissue plays an important role in the development of metabolic disturbances, a characteristic feature of chronic kidney disease （CKD）. In the present study, we tested the hypothesis that the inhibition of endoplasmic reticulum （ER） stress could alleviate lipolysis in white adipose tissue in a rat model of CKD. Methods： A rat model of CKD was established by a method of reduced renal mass （RRM）. Lipolysis was measured as the release of glycerol in ex vivo fat pads and cultured primary adipocytes. The activity of lipases and markers of ER stress were measured by Western blotting and immunoprecipitation. Results; Our data showed that lipolysis in visceral white adipose tissue was increased in RRM rats compared with control rats. In addition, increased phosphorylation of hormone-sensitive lipase （HSL） and binding of adipose triglyceride lipase （ATGL） to comparative gene identification-58 （CGI-58） protein were observed in the RRM rats. The phosphorylation of ER stress markers, including IREla, PERK, and eukaryotic initiation factor （elF） 2a, and the expression of ER stress marker 78 kDa glucose-regulated protein （GRP78） were significantly increased in RRM rats. Treatment with an inhibitor of ER stress partially but significantly alleviated lipolysis, and this alleviation was accompanied by reduced binding of ATGL to CGI-58. Conclusion： Our results showed that enhanced lipolysis and ER stress occurred in visceral white adipose tissue in a rat model of CKD. Moreover, inhibition of ER stress significantly alleviated lipolysis. These findings suggest that ER stress is a potential therapeutic target for the metabolic disturbances associated with CKD.