Sex- and age-dependent effects of maternal organophosphate flame-retardant exposure on neonatal hypothalamic and hepatic gene expression

After the phase-out of polybrominated diphenyl ethers, their replacement compounds, organophosphate flame retardants (OPFRs) became ubiquitous in home and work environments. OPFRs, which may act as endocrine disruptors, are detectable in human urine, breast milk, and blood samples collected from pregnant women. However, the effects of perinatal OPFR exposure on offspring homeostasis and gene expression remain largely underexplored. To address this knowledge gap, virgin female mice were mated and dosed with either a sesame oil vehicle or an OPFR mixture (tris(1,3-dichloro-2-propyl)phosphate, tricresyl phosphate, and triphenyl phosphate, 1 mg/kg each) from gestational day (GD) 7 to postnatal day (PND) 14. Hypothalamic and hepatic tissues were collected from one female and one male pup per litter on PND 0 and PND 14. Expression of genes involved in energy homeostasis, reproduction, glucose metabolism, and xenobiotic metabolism were analyzed using quantitative real-time PCR. In the mediobasal hypothalamus, OPFR increased Pdyn, Tac2, Esr1, and Pparg in PND 14 females. In the liver, OPFR increased Pparg and suppressed Insr, G6pc, and Fasn in PND 14 males and increased Esr1, Foxo1, Dgat2, Fasn, and Cyb2b10 in PND 14 females. We also observed striking sex differences in gene expression that were dependent on the age of the pup. Collectively, these data suggest that maternal OPFR exposure alters hypothalamic and hepatic development by influencing neonatal gene expression in a sex-dependent manner. The long-lasting consequences of these changes in expression may disrupt puberty, hormone sensitivity, and metabolism of glucose, fatty acids, and triglycerides in the maturing juvenile.     

Increased adiposity on normal diet, but decreased susceptibility to diet-induced obesity in mu-opioid receptor-deficient mice

The mu-opioid receptor encoded by the Oprm1 gene plays a crucial role in the mediation of food reward and drug-induced positive reinforcement, but its genetic deletion has been shown to provide food intake-independent, partial protection from diet-induced obesity. We hypothesized that mu-opioid receptor-deficient mice would show an even greater, intake-dependent, resistance to high-fat diet-induced obesity if the diet comprises a sweet component. We generated an F2 population by crossing the heterozygous offspring of homozygous female Oprm1(-/-) mice (on a mixed C57BL/6 and BALB/c genetic background) with male inbred C57BL/6 mice. Groups of genotyped wild-type (WT) and homozygous mutant (KO) males and females were fed either control chow or a high caloric palatable diet consisting of sweet, liquid chocolate-flavored Ensure together with a solid high-fat diet. Food intake, body weight, and body composition was measured over a period of 16 weeks. Unexpectedly, male, and to a lesser extent female, KO mice fed chow for the entire period showed progressively increased body weight and adiposity while eating significantly more chow. In contrast, when exposed to the sweet plus high-fat diet, male, and to a lesser extent female, KO mice gained significantly less body weight and fat mass compared to WT mice when using chow fed counterparts for reference values. Male KO mice consumed 33% less of the sweet liquid diet but increased intake of high-fat pellets, so that total calorie intake was not different from WT animals. These results demonstrate a dissociation of the role of mu-opioid receptors in the control of adiposity for different diets and sex. On a bland diet, normal receptor function appears to confer a slightly catabolic predisposition, but on a highly palatable diet, it confers an anabolic metabolic profile, favoring fat accretion. Because of the complexity of mu-opioid gene regulation and tissue distribution, more selective and targeted approaches will be necessary to fully understand the underlying mechanisms.     

Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice

Background and Purpose

Systemic oxidative stress associated with dietary calorie overload plays an important role in the deterioration of vascular function in middle-aged patients suffering from obesity and insulin resistance. However, effective therapy is still lacking.

Experimental Approach

In this study, we used a mouse model of middle-aged obesity to investigate the therapeutic potential of pharmaceutical inhibition (apocynin, 5 mM supplied in the drinking water) or knockout of Nox2, an enzyme generating reactive oxygen species (ROS), in high-fat diet (HFD)–induced obesity, oxidative stress, insulin resistance and endothelial dysfunction. Littermates of C57BL/6J wild-type (WT) and Nox2 knockout (KO) mice (7 months old) were fed with a HFD (45% kcal fat) or normal chow diet (NCD, 12% kcal fat) for 16 weeks and used at 11 months of age.

Key Results

Compared to NCD WT mice, HFD WT mice developed obesity, insulin resistance, dyslipidaemia and hypertension. Aortic vessels from these mice showed significantly increased Nox2 expression and ROS production, accompanied by significantly increased ERK1/2 activation, reduced insulin receptor expression, decreased Akt and eNOS phosphorylation and impaired endothelium-dependent vessel relaxation to acetylcholine. All these HFD-induced abnormalities (except the hyperinsulinaemia) were absent in apocynin-treated WT or Nox2 KO mice given the same HFD.

Conclusions and Implications

In conclusion, Nox2-derived ROS played a key role in damaging insulin receptor and endothelial function in dietary obesity after middle-age. Targeting Nox2 could represent a valuable therapeutic strategy in the metabolic syndrome.     

Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet

Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulating glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling.     

Effects of deoxynivalenol consumption on body weight and adiposity in the diet-induced obese mouse

The potential for the obese state to alter sensitivity to toxic chemicals is poorly understood. In this study, dose-response effects of the trichothecene deoxynivalenol (DON), a common food-borne mycotoxin, were determined on body weight of diet-induced obese mice. In study 1, the effects of feeding adult female B6C3F1 mice a high-fat diet (HFD; 60% kcal from fat) containing 0, 2, 5, or 10 ppm DON for 10 wk on body weight and adiposity were compared. Mice consuming 5 or 10 ppm DON exhibited a 15 and 24% decrease in weight gain and a 50 and 83% reduction in periuterine fat, respectively. In study 2, mice were fed HFD for 8 wk to induce obesity and the effects of consuming HFD + 0, 2, 5, or 10 ppm DON for 8 wk were then determined. Mice fed 5 or 10 ppm DON exhibited a 16 and 23% weight reduction and a 0 and 40% periuterine fat reduction, respectively. In a follow-up experiment, food consumption was measured prior to and after the transition from HFD to HFD + 10 ppm DON. Exposure to DON was found to lower HFD consumption within 1 d, with significant weight loss in DON-fed mice evident after 6 d. In both studies 1 and 2, consumption of 5 or 10 ppm DON diminished circulating levels of insulin-like growth factor acid-labile subunit. Taken together, DON consumption lowered weight gain and produced weight loss in diet-induced obese mice at higher thresholds than that observed previously in normal B6C3F1 mice.     

The effect of high-fat diet-induced obesity on cardiovascular toxicity in Wistar albino rats

The consumption of a high-fat diet (HFD) is considered a risk factor for obesity development. Nonetheless, a causal role of dietary fat has never been documented, because of inadequate animal models. In our study, one group of rats was fed with standard rat diet, while other group of rats fed with high-fat diet for 4 weeks. After 4 weeks of feeding, the hemodynamic parameters in the rats fed with HFD were significantly increased as compared with control rats. Rats fed with HFD had elevated levels of serum lipids, insulin, leptin, glucose and apolipoprotein B. Lipid peroxides and caspase-3 levels were increased while serum apolipoprotein A1 and antioxidant enzymes levels in heart tissues were decreased in HFD-induced obesity in rats as compared to normal healthy control rats fed on standard rat pellet diet. This model of diet-induced obesity will be a useful tool for studying the mechanisms by which dietary fat induces the obesity in humans.     

Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells

Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP), and 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.     

Resting energy expenditure and insulin resitance in obese patients, differences in women and men

BACKGROUND AND OBJECTIVE: There is little research about the relation of REE and insulin resistance with gender. The aim of our work was to study gender differences in REE and insulin resistance in obese patients. RESEARCH METHODS AND PROCEDURES: A population of 131 obesity patients was analyzed in a prospective way. The following variables were specifically recorded: age, smoking habit, drinking habit, weight, body mass index (BMI), waist circumference, and waist-hip ratio. Blood pressure, basal glucose, insulin, fibrinogen, and C-reactive protein. HOMA was calculated. An indirect calorimetry, tetrapolar electrical bioimpedance and a serial assessment of nutritional intake with 3 days written food records were performed. RESULTS: The mean age was 31.7 +/- 9.2 years and the mean BMI 34.4 +/- 5.3. Cardiovascular risk factors were similar in both groups. Anthropometric measurements showed an average waist circunference (107.8 +/- 16.1 cm), waist-to hip ratio (0.93 +/- 0.11), and average weight (94.8 +/- 20.2 kg). Bipolar body electrical bioimpedance showed the next data; fat free mass (55.2 +/- 17.1 kg) and fat mass (35.7 +/- 12.3 kg). Indirect calorimetry showed higher resting metabolic rate (REE) in males (2001.7 +/- 443 Kcal/day vs. 1774.7 +/- 344 Kcal/day; p < 0.05). REE corrected by fat free mass was similar (male 34.2 +/- 17 Kcal/day/kg vs female 39 +/- 11.6 Kcal/day/kg; ns). Nutritional intake and HOMA were similar in males and females. In the multivariate analysis with a dependent variable (RMR), the fat free mass remained in the male model (F = 18.5; p < 0.05), with an increase of 17.8 (CI 95%: 9.1-26.2) kcal/day with each 1 kg of fat free mass adjusted by age. In the female model, the fat free mass remained in the model (F = 1 2.5; p < 0.05), with an increase of 15.2 (CI 95%: 6.3-24.2) kcal/day with each 1 kg of fat free mass adjusted by age. CONCLUSION: REE was higher in males than females, with a higher influence of fat free mass in males than females. No association between insulin resistance and REE was detected.     

Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice

Ezetimibe is a novel cholesterol and plant sterol absorption inhibitor that reduces plasma low-density lipoprotein-cholesterol by selectively binding to the intestinal cholesterol transporter, Niemann-Pick C1-Like 1. Mice deficient in Niemann-Pick C1-Like 1 are protected from high fat/cholesterol diet-induced fatty liver as well as hypercholesterolemia. The object of the present study was to determine whether ezetimibe treatment could reduce hepatic steatosis in diet-induced obese mice. C57BL/6J mice were fed a high fat/cholesterol containing semi-purified diet (45% Kcal fat and 0.12% cholesterol) for 7 months after weaning. These mice were not only obese, but also developed hepatomegaly and hepatic steatosis, with varying degrees of liver fibrosis and steatohepatitis. About 87% of the mice on the high fat/cholesterol diet for 7 months had elevated plasma alanine aminotransferase activity, a biomarker for non-alcoholic fatty liver disease. Chronic administration of ezetimibe for 4 weeks significantly reduced hepatomegaly by decreasing hepatic triglyceride, cholesteryl ester and free cholesterol in diet-induced obese mice fed high fat/cholesterol diet for 7 months. Chronic ezetimibe treatment also significantly decreased plasma alanine aminotransferase activity. These results suggest that ezetimibe may be a novel treatment for high fat/cholesterol-induced non-alcoholic fatty liver disease.     

TCDD-induced anorexia and wasting syndrome in rats: effects of diet-induced obesity and nutrition

Interactions of diet and diet-induced obesity, and the characteristic wasting syndrome caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in TCDD-resistant Han/Wistar and TCDD-sensitive Long-Evans rats. The rats were made obese by feeding them either a high-energy diet (consisting of chocolate, cheese, and chow) or force feeding. TCDD reduced body weight in a parallel manner in lean and obese rats. The high-energy diet diminished the body weight loss and increased the survival time in L-E rats after a lethal dose of TCDD, while energy supplement with high-fat/low-protein food had an opposite effect. In conclusion, diet-induced obesity and TCDD had additive effects on body weight. Dietary manipulations were able to modify the weight loss and survival time after TCDD. Fat seems to have a negative impact, while carbohydrate or protein may have a positive impact in this respect. The results are in agreement with a view that TCDD-exposed rats have a negative fat balance favoring fat loss.     

Role and mechanism of ORM in adipose tissue fibrosis and insulin resistance in obese mice

OBJECTIVE During the development of obesity, adipose tissue fibrosis occurs as a hallmark of adipose tissue dysfunction, leading to metabolic dysfunction such as insulin resistance. We previously reported adipokine orosomucoid(ORM) could be a negative feedback signal in energy homeostasis, and its level was significantly elevated in response to obese state. Here we aimed to explore the role of ORM in adipose tissue fibrosis and insulin resistance during obesity, and its possible mechanism. METHODS MRI was used to assess the distribution of fat and the fat or lean mass in ORM1 knockout mice. HE staining, masson staining, qPCR, and Western blotting were used to assess the fibrosis status of mice. And we used glucose tolerance test(GTT) and insulin tolerance test(ITT) to evaluate the regulation of blood glucose and insulin sensitivity in mice. Leptin receptor-deficient db/db mice and high fat diet-induced obese mice were used as obese models. 3 T3-L1 cells were used in vitro. RESULTS ORM1-deficient mice exhibited an obese phenotype with adipose tissue fibrosis and insulin resistance. The m RNA and protein levels of the fibrogenic genes encoding Col1a1, Col3a1, Col6a3 and ECM regulators MMP-2, MMP-13, MMP-14 TIMP-1,TIMP-2, and TIMP-3 in ORM1-deficient mice were significantly increased. GTT and ITT showed abnormal glucose tolerance and insulin resistance in ORM1-deficient mice.Moreover, exogenous administration of ORM attenuated excessive expression of type Ⅵ collagen, MMP-13 and TIMP-1 induced by adipose fibrosis in obese db/db(lep Rdeficient) mice. GTT and ITT showed ORM treatment improved insulin resistance in db/db mice. Moreover,ORM synergized with insulin to activate Akt in adipose tissue of db/db mice. Further studies found that ORM could bind to C-C chemikine receptor 5(CCR5) and ORM improves insulin resistance in high fat diet-induced obese mice, which could be blocked by maraviroc, an antagonist against CCR5. In addition, the effect of ORM in synergy with insulin to activate Akt in adipose tissue of db/db mice was also abolished by maraviroc. We also found that ORM stimulated AMPK activity and inhibits the TGF-β_1 expression in adipose tissue of db/db mice,thereby attenuating adipose tissue fibrosis. In vitro, ORM treatment also alleviated abnormal expression of fibrogetic genes in 3 T3-L1 fibroblasts induced by TGF-β_1. Of note,the inhibitory effects of ORM on fibrosis were abolished by dorsomorphin, a selective inhibitor of AMPK. CONCLUSION ORM alleviates adipose tissue fibrosis and insulin resistance through CCR5. ORM is expected to be a novel target for the treatment of obesity and its related diseases.     

Hypoglycemic and antioxidative effects of hydroxyethyl methylcellulose in mice fed with high fat diet

The effect of hydroxyethyl methylcellulose (HEMC) with different viscosities on the glucose metabolism and antioxidative defense system in high fat-fed mice was investigated. The mice were randomly divided into five dietary groups: normal control diet (NC), high fat diet (HF), and high fat diet supplemented with high viscosity (HF-HV), moderate viscosity (HF-MV), and low viscosity (HF-LV) HEMC fibers. After 6 weeks, the HF group showed a marked increase in body weight gain, body fat, blood glucose concentration, insulin level, and erythrocyte lipid peroxidation rate relative to the NC group. However, supplementation of HEMC in the diet suppressed these high fat-induced hyperglycemia and oxidative stress through enhancement of the activities of hepatic glucokinase and antioxidant enzymes. The hypoglycemic and antioxidative effects increased with increased viscosity of the HEMC consumed. These results illustrate that HEMC with high viscosity may be useful in the management of high fat diet-induced hyperglycemia and oxidative stress.     

Protein tyrosine phosphatase 1B as a target for the treatment of impaired glucose tolerance and type II diabetes

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signal transduction cascade, initiated when insulin binds to the insulin receptor. PTP1B-deficient mice are more sensitive to insulin, and have improved glycemic control and resistance to diet-induced obesity than wild-type control mice. Diabetic mice treated with PTP1B antisense oligonucleotides intraperitoneally have lower PTP1B protein levels in liver and fat, reduced plasma insulin, blood glucose and hemoglobin A1c (HbA1c) levels. These studies validate PTP1B as a promising drug discovery target for the treatment of insulin resistance, diabetes and obesity. Herein we review the recent advances in the structure-based design of potent and selective small molecule inhibitors of PTP1B, and discuss th e challenge of developing compounds with improved cell permeability and bioavailability.     

Pandanus amaryllifoliusleaf extract improves insulin sensitivity in high-fat diet-induced obese mice

OBJECTIVE To investigate the effect of Pandanus amaryllifolius leaf in high-fat diet-induced insulin resistance in mice model.METHODS To induce obesity,male ICR mice were fed with a high-fat diet(45%fat)for six weeks.The mice were divided into four groups(n=8):non-obese control mice were treated with 5% gum arabic and obese mice were treated with Pandanus amaryllifolius(125and 250mg·kg-1·d-1),or 5% gum arabic.After six weeks of treatments,the fasting blood glucose,serum insulin,OGTT and fat cell protein expression of glucose transporter 4(GLUT4)were determined.RESULTS Administration of Pandanus amaryllifolius showed significantly(P<0.05)reduced the high blood glucose,inhibited the abnormal increase in blood glucose level during OGTT,and decreased the high level of serum insulin.Moreover,it is interesting that the protein expression of GLUT4 was effectively increased by Pandanus amaryllifolius.CONCLUSION These findings demonstrate that the extract from Pandanus amaryllifolius leaf possesses antihyperglycemic action in obese mice by improving insulin sensitivity and stimulating GLUT4 expression in adipose tissue.     

中度限食对肥胖小鼠胰岛β细胞分泌功能的影响

摘要： 目的 明确中度限食干预能否从形态和功能上逆转肥胖对胰岛β细胞的损伤。方法 4周龄雄性C57BL/6 小鼠喂以高脂饮食8周, 建立饮食诱导的肥胖模型, 随后进行3周的高脂转普食 （HF→NC组） 或在此基础上40%限食干预 （HF→NC CR组）, 同时设高脂对照组 （HF AL组） 和普食对照组 （NC AL组）, 每组20只。实验终点取胰腺组织行胰岛素免疫组化染色, 定量β细胞面积, 并行腹腔葡萄糖耐量试验及胰岛素耐量试验, 评估早时相和第二时相胰岛素分泌及胰岛素敏感性。同时, 分离小鼠胰岛, 行静态葡萄糖刺激的胰岛素分泌实验及胞浆胰岛素含量测定。结果 实验终点HF AL组表现为显著肥胖、 β细胞面积增加、 糖耐量受损、 早时相胰岛素分泌趋向降低及胰岛素抵抗, 同时离体胰岛实验显示胞浆胰岛素含量增加, 但胰岛素分泌缺陷： 基础胰岛素分泌升高了30.6%, 而16.7 mmol/L高糖刺激下的胰岛素分泌降低了52.1%。HF→NC组小鼠的糖耐量恢复正常, 体质量有所降低但未正常, 早时相胰岛素分泌及离体胰岛高糖刺激的胰岛素分泌较HF AL组并无改善。经过3周的限食干预, HF→NC CR组体质量、 β细胞面积、糖耐量、 早时相胰岛素分泌、 胰岛素敏感性及离体胰岛基础和高糖刺激下的胰岛素分泌均恢复正常。结论 中度（40%） 限食干预至体质量正常, 可逆转饮食诱导肥胖小鼠的胰岛β细胞分泌功能紊乱, 重建葡萄糖稳态。     

Effects of escin mixture from the seeds of Aesculus hippocastanum on obesity in mice fed a high fat diet

Escins, a triterpene glycoside mixture obtained from the ethanol extract of Aesculus hippocastanum L. (Hippocastanaceae) seed, was evaluated for its in vivo effects on the plasma levels of some hormones (leptin, insulin, FT₃, FT₄) and biochemical parameters (glucose, triglyceride, total cholesterol, HDL-C, LDL-C concentrations) in mice fed with a high fat diet for 5 weeks. A high fat diet induced a remarkable increment in the plasma leptin (p <0.01), total cholesterol (p <0.01) and LDL-C (p <0.001) concentrations compared to control group animals. Combined administration of a high-fat diet with escins decreased leptin (31.6%) (p<0.05) and FT₄ (36.0%) (p<0.05) levels, increased HDL-C concentration (17.0%), while remained ineffective on LDL-C concentration in mice. Results have shown that escins may have beneficial effects in the understanding of 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.