Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice

OBJECTIVE: To investigate the development of high fat diet-induced obesity and leptin resistance. DESIGN: Two experiments were carried out in this study. Firstly, we fed the mice with a high- or low-fat diet for up to 19 weeks to examine a progressive development of high fat diet-induced obesity. Secondly, we examined peripheral and central exogenous leptin sensitivity in mice fed high- or low-fat diets for 1, 8 or 19 weeks. SUBJECTS: A total of 168 C57BL/6J mice (3 weeks old) were used in this study. MEASUREMENTS: In the first experiment, we measured the body weight, energy intake, adipose tissue mass, tibia bone length, and plasma leptin in mice fed either a high- or low-fat diet for 1, 8, 15 and 19 weeks. In the second experiment, body weight change and cumulative energy intake were measured at 6 h intervals for 72 h after leptin injection in mice fed a high- or low-fat diet for 1, 8 or 19 weeks. RESULTS: The results from the first experiment suggested that the development of high fat diet-induced obesity in mice could be divided into early, middle and late stages. Compared with the mice fed a low-fat diet, the mice fed a high-fat diet showed a gradually increased body weight (+5.2%), fat storage (epididymal plus perirenal; +6.7%) and plasma leptin (+18%) at 1 week; +11.4%, +68.1%, and +223%, respectively, at 8 weeks; and +30.5%, +141%, and +458%, respectively, at 19 weeks. Energy intake of high fat diet-fed mice was equal to that of low fat diet-fed controls for the first 3 weeks; it fell below control levels over the next 5 week period, but began to increase gradually after 8 weeks of high-fat diet feeding and then increased dramatically from 15 weeks to be 14% higher than that of controls after 19 weeks. The results from our second experiment showed that: (1) after 1 week of feeding, the mice fed a high-fat diet were sensitive to a 2 microg/g (body weight) intraperitoneal (i. p.) injection of leptin, with no differences in body weight change or cumulative energy intake post-injection; (2) after 8 weeks of feeding, the mice fed a high-fat diet were insensitive to 2 microg/g (body weight) i.p. leptin, but were sensitive to a 0.1 microg intracerebroventricular (i.c.v.) injection of leptin; (3) after 19 weeks of feeding, the mice fed a high-fat diet were insensitive to 0. 1 microg i.c.v. leptin, but were sensitive to a high dose of 2 microg i.c.v. leptin. CONCLUSIONS: The present study demonstrated that the development of high fat diet-induced obesity (19 weeks) in C57 B1/6J mice could be divided into three stages: (1) an early stage in response to high-fat diet that mice were sensitive to exogenous leptin; (2) a reduced food intake stage when mice had an increase in leptin production and still retained central leptin sensitivity; and (3) an increased food intake stage, accompanied by a reduction of central leptin sensitivity.     

Anti-obesity effects in rodents of dietary teasaponin, a lipase inhibitor.

OBJECTIVE: Based on the inhibitory effects of teasaponin on pancreatic lipase activity in vitro, this study was performed to clarify whether teasaponin prevented obesity induced in mice by a high-fat diet for 11 weeks. DESIGN: For in vitro experiments, assay for the inhibitory effects of teasaponin on pancreatic lipase activity was performed by measuring the rate of release of oleic acid from triolein in an assay system using triolein emulsified with lecithin, gum arabic, Triton X-100 or 4-methylumbelliferyloleate. For in vivo experiments, female ICR mice were fed a high-fat diet with or without 0.5% teasaponin for 11 weeks. RESULTS: Teasaponin competitively inhibited the hydrolysis of triolein emulsified with lecithin, gum arabic, Triton X-100 or 4-methylumbelliferyloleate. Teasaponin inhibited the elevations of plasma triacylglycerol levels 3, 4 and 5 h after oral administration of lipid emulsion containing corn oil. Teasaponin suppressed the increases in body, parametrial adipose tissue weights and diameter in adipose cell size induced by a high-fat diet. Furthermore, feeding a high-fat diet plus teasaponin had no effect on stool frequency and content, but significantly increased triacylglycerol contents in feces as compared to feeding a high-fat diet. CONCLUSIONS: The anti-obesity effects of teasaponin in high-fat diet-treated mice may be partly mediated through delaying the intestinal absorption of dietary fat by inhibiting pancreatic lipase activity.     

Hyperleptinemia precipitates diet-induced obesity in transgenic mice overexpressing leptin

Transgenic mice overexpressing leptin backcrossed to the C57BL/6J genetic background (LepTg) have a lean phenotype, characterized by a 95% reduction in adipose mass; reduced plasma levels of glucose, triglycerides, insulin, and IGF-1; and a 75% decrease in adipocyte size. High-fat diet treatment for 20 wk revealed that, compared with normal mice, the LepTg mice had an increased susceptibility to diet-induced obesity, as demonstrated by their rate of weight gain, higher accumulation of sc white adipose tissue mass, hypertrophy of adipocytes, and normalization of their reduced metabolic parameters. The stromal vascular fraction of white adipose tissue from the LepTg mice was highly cellular and contained cells capable of rapid lipid accumulation in primary cultures. The precipitous diet-induced obesity of the LepTg mice was accompanied with 10-fold and 1.6-fold elevations in insulin and IGF-1, respectively, suggesting that the trophic action of insulin and IGF-1 on the preadipocytes and small adipocytes may have caused them to rapidly differentiate and accumulate triacylglycerol stores. Other contributing factors may involve a shift in insulin sensitivity triggered by hyperleptinemia and a decrease in energy expenditure. These studies demonstrate that a chronic response to hyperleptinemia as in the LepTg mice is a predisposing factor to diet-induced obesity and suggest that individuals who are particularly lean because of increased leptin secretion may develop rapid obesity under conditions of a high-fat diet.     

Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice

Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARalpha target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice.     

Beneficial effects of tea catechins on diet-induced obesity: stimulation of lipid catabolism in the liver

OBJECTIVE: Obesity has increased at an alarming rate in recent years and is now a worldwide health problem. We investigated the effects of long-term feeding with tea catechins, which are naturally occurring polyphenolic compounds widely consumed in Asian countries, on the development of obesity in C57BL/6J mice. DESIGN: We measured body weight, adipose tissue mass and liver fat content in mice fed diets containing either low-fat (5% triglyceride (TG)), high-fat (30% TG), or high-fat supplemented with 0.1-0.5% (w/w) tea catechins for 11 months. The beta-oxidation activities and related mRNA levels were measured after 1 month of feeding. RESULTS: Supplementation with tea catechins resulted in a significant reduction of high-fat diet-induced body weight gain, visceral and liver fat accumulation, and the development of hyperinsulinemia and hyperleptinemia. Feeding with tea catechins for 1 month significantly increased acyl-CoA oxidase and medium chain acyl-CoA dehydrogenase mRNA expression as well as beta-oxidation activity in the liver. CONCLUSION: The stimulation of hepatic lipid metabolism might be a factor responsible for the anti-obesity effects of tea catechins. The present results suggest that long-term consumption of tea catechins is beneficial for the suppression of diet-induced obesity, and it may reduce the risk of associated diseases including diabetes and coronary heart disease.     

Adipose triglyceride lipase-null mice are resistant to high-fat diet-induced insulin resistance despite reduced energy expenditure and ectopic lipid accumulation

Adipose triglyceride lipase (ATGL) null (-/-) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL-/- mice persist when challenged with a high-fat diet. ATGL-/- mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL-/- mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre-high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet-induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet-induced insulin resistance in ATGL-/- mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL-/- mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.     

Anti-obesity effects of lipase inhibitor CT-II, an extract from edible herbs, Nomame Herba, on rats fed a high-fat diet

OBJECTIVE: To investigate the inhibitory effects of CT-II, extract of Nomame Herba, on lipase activity in vitro and on obesity in rats fed a high-fat diet in vivo. DESIGN: The assay for the inhibitory effect of CT-II on lipase activity was performed by measuring released free fatty acids after the incubation of the medium with CT-II, porcine pancreatic lipase and triolein (experiment 1). In vivo experiments, lean rats or obese rats (570-718 g) were fed a high-fat diet containing 60% fat with or without CT-II for 8 weeks (experiment 2), for 14 days (experiment 3) or for 12 weeks (experiment 4), respectively. MEASUREMENT: The time course of body weight, food intake, organ weight (parametrial fat, liver, heart and kidney) and plasma parameters (triglyceride, total cholesterol, glucose, AST, ALT and insulin), fecal output of total fat and total cholesterol were measured. Hepatic histological examinations were also performed. RESULTS: CT-II inhibited the porcine lipase activity dose-dependently in vitro (experiment 1). Body and liver weight were reduced and hepatic histological examination showed an amelioration of fatty liver in CT II treated animals (experiment 2). CT-II significantly inhibited body weight gain and plasma triglyceride elevation in a dose-dependent manner, without affecting food intake in lean rats fed the high-fat diet. Elevated plasma AST and ALT were also decreased (experiment 3). When obese rats fed the high-fat diet were treated with CT-II for up to 6 months, body weight was initially reduced and thereafter weight gain was significantly suppressed. Total body fat was also significantly reduced and significant reduction of plasma AST and ALT was observed (experiment 4). CONCLUSIONS: These results demonstrated that the lipase inhibitor CT-II is effective in preventing and ameliorating obesity, fatty liver and hypertriglyceridemia in rats fed a high-fat diet.     

Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice

Liver fatty acid-binding protein (L-Fabp) regulates murine hepatic fatty acid trafficking in response to fasting. In this study, we show that L-Fabp(-/-) mice fed a high-fat Western diet for up to 18 weeks are less obese and accumulate less hepatic triglyceride than C57BL/6J controls. Paradoxically, both control and L-Fabp(-/-) mice manifested comparable glucose intolerance and insulin resistance when fed a Western diet. Protection against obesity in Western diet-fed L-Fabp(-/-) mice was not due to discernable changes in food intake, fat malabsorption, or heat production, although intestinal lipid secretion kinetics were significantly slower in both chow-fed and Western diet-fed L-Fabp(-/-) mice. By contrast, there was a significant increase in the respiratory exchange ratio in L-Fabp(-/-) mice, suggesting a shift in energy substrate use from fat to carbohydrate, findings supported by an approximately threefold increase in serum lactate. Microarray analysis revealed increased expression of genes involved in lipid synthesis (fatty acid synthase, squalene epoxidase, hydroxy-methylglutaryl coenzyme A reductase), while genes involved in glycolysis (glucokinase and glycerol kinase) were decreased in L-Fabp(-/-) mice. Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice. In conclusion, L-Fabp may function as a metabolic sensor in regulating lipid homeostasis. We suggest that L-Fabp(-/-) mice are protected against Western diet-induced obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use. (HEPATOLOGY 2006;44:1191-1205.).     

Dietary 1,3-diacylglycerol protects against diet-induced obesity and insulin resistance

To investigate the effect of dietary 1,3-diacylglycerol (DAG) on the development of insulin resistance (IR) and obesity, brown adipose tissue-deficient mice, a model of high-fat diet-induced IR and obesity, were fed Western-type diets (WTD) containing either DAG oil (n = 8) or standard triacylglycerol (TAG) oil (n = 9) for 15 weeks, beginning at 8 weeks of age. Although brown adipose tissue-deficient mice became obese on both TAG- and DAG-enriched WTD (TAG-WTD and DAG-WTD), the mice eating DAG-WTD gained less weight and had less body fat accumulation. The results of glucose tolerance tests conducted after 5 weeks of each WTD were not different. However, after 10 weeks of each WTD, impaired glucose tolerance developed in the TAG-WTD group but was prevented by DAG-WTD. Exploratory analyses of gene expression suggested that consumption of DAG-WTD was associated with reduced phosphoenolpyruvate carboxykinase gene expression in liver and increased expression of the genes for peroxisome proliferator-activated receptor alpha, lipoprotein lipase, and uncoupling proteins 2 and 3 in skeletal muscle. There were no effects of the DAG-WTD on fasting and postprandial plasma triglyceride (TG) levels, hepatic TG content, or the rate of secretion of TG from the liver. These findings suggest that diets enriched in 1,3-DAG oil may reduce WTD-induced IR and body fat accumulation by suppressing gluconeogenesis in liver and stimulating fat oxidation in skeletal muscle.     

Change of cytokine balance in diet-induced obese mice

Although decreased T-cell function has been observed in obese human subjects and genetically obese animals, the precise role of immune functions in obesity is still unclear. To investigate immune functions in obesity, we examined the proliferative responses of splenic lymphocytes and their capacity to produce cytokines in the presence or absence of leptin, the protein produced by the obese gene, in diet-induced obese and control mice. For induction of obesity, C57BL/6J mice were fed a high-fat diet for 13 weeks. In mice fed the high-fat diet, body weight, fat pad weight, and tumor necrosis factor (TNF) alpha production by adipocytes were significantly increased relative to mice fed the normal diet. Lipopolysaccharide (LPS) stimulated proliferation of cultured splenocytes from diet-induced obese mice was also increased. However, production of interleukin (IL)-2 by splenic lymphocytes from obese mice was suppressed, whereas interferon (IFN)-gamma and IL-4 production was increased. Exogenous lepitn regulated the cytokine production by cultured splenocytes from control and obese mice, respectively (upregulation of IFN-gamma and downregulation of IL-2 in control mice, and downregulation of IL-4 in obese mice). These results suggest that changes in cytokine production by splenic lymphocytes in obesity are indicative of altered immune functions that might contribute to related complications, although the effect of difference in nutrient intake (macro and micro) may also have contributed to the changes.     

Reduction of diet-induced obesity by a combination of tea-catechin intake and regular swimming

OBJECTIVE: Obesity is a metabolic disorder resulting from imbalance between metabolizable energy intake and energy expenditure. It is known to be a strong risk factor for lifestyle-related diseases. Here, we investigated the effects of long-term intake of tea catechins (Cat) in combination with regular exercise (Ex) on the development of obesity in C57BL/6 mice. DESIGN: We compared body weight, adipose tissue mass, plasma parameters and beta-oxidation activity in mice fed a low-fat diet (5% triglyceride (TG); LF), a high-fat diet (30% TG; HF), a HF diet supplemented with 0.5% (w/w) tea Cat, a HF diet in addition to swimming Ex or a HF diet plus 0.5% tea Cat in addition to swimming Ex (Cat+Ex) for 15 weeks. Oxygen consumption and respiratory quotients were measured using indirect calorimetry. RESULTS: Tea-Cat intake in combination with swimming Ex suppressed HF diet-induced body-weight gain by 18 and 22%, respectively, compared to Ex and tea-Cat intake on their own. Visceral fat accumulation and the development of hyperinsulinemia and hyperleptinemia were also reduced in the HF+Cat+Ex group. Muscular beta-oxidation activity in this group was 69 and 52% higher, respectively, than that in the HF and HF+Cat groups. Lipid oxidation, determined using indirect calorimetry, was higher in the HF+Cat+Ex group, suggesting increased lipid utilization at the individual level. CONCLUSION: These results indicate that intake of tea Cat, together with regular Ex helps to reduce diet-induced obesity. This effect might be attributed, at least in part, to the activation of whole-body energy metabolism.     

High-fat diet enhances visceral advanced glycation end products, nuclear O-Glc-Nac modification, p38 mitogen-activated protein kinase activation and apoptosis

High-fat diet intake often leads to obesity, insulin resistance and hypertension, which present a common and detrimental health problem. However, precise mechanism underlying tissue damage due to high-fat diet-induced obesity has not been carefully elucidated. The present study was designed to examine the effect of high-fat diet intake on visceral advanced glycation end products (AGEs) formation, nuclear O-Glc-NAc modification and apoptosis in heart, liver and kidney. Adult male Sprague-Dawley weight-matched rats were fed for 12 weeks with a high-fat diet (45% kcal from fat) or an isocaloric low-fat diet (10% kcal from fat). High-fat diet feeding significantly elevated body weight. Blood pressure and heart rate were comparable between the two rat groups. Competitive enzyme-linked immunosorbent assay showed significantly elevated serum AGE levels, visceral AGE formation, caspase-3 activation and cytoplasmic DNA fragmentation in heart and liver but not kidney samples of high-fat diet fed rats compared with those from low-fat diet fed group. Western blot analysis further revealed that high-fat diet feeding induced overt nuclear O-Glc-NAc modification and p38 mitogen-activated protein kinase activation in heart and liver although not in kidney samples of the high-fat diet-fed rats. Collectively, our results indicated that high-fat diet intake is associated with obesity accompanied by elevated serum and visceral AGEs, visceral post-translational nuclear O-Glc-NAcylated modification and apoptosis, which may contribute to high-fat diet-induced tissue damage.     

TEAVIGO (epigallocatechin gallate) supplementation prevents obesity in rodents by reducing adipose tissue mass

BACKGROUND: This study investigated the antiobesity effects of TEAVIGO, a product providing the most abundant green tea catechin, epigallocatechin gallate (EGCG), in a pure form. Two models of diet-induced obesity and an in vitro adipocyte differentiation assay were employed. METHODS: Prevention and regression of diet-induced obesity by dietary supplementation with EGCG was studied in C57BL/6J mice and Sprague-Dawley rats, respectively. Expression of genes regulating lipid metabolism was assessed in adipose tissue. The effects of EGCG on adipocyte differentiation were investigated in vitro. RESULTS: In C57BL/6J mice, EGCG supplementation prevented diet-induced increases in body weight and in fed state plasma levels of glucose, triglycerides, and leptin. EGCG decreased subcutaneous and epididymal adipose tissue weights. Supplementation of EGCG reversed the established obesity in Sprague-Dawley rats. Fatty acid synthase and acetyl-CoA carboxylase-1 mRNA levels were markedly decreased in adipose tissue of EGCG-supplemented mice. EGCG dose dependently inhibited adipocyte differentiation in vitro. CONCLUSION: This study shows for the first time that supplementation with the most abundant green tea polyphenol, EGCG, abolishes diet-induced obesity. This effect is at least partly mediated via a direct influence on adipose tissue. Thus, dietary supplementation with EGCG should be considered as a valuable natural treatment option for obesity.     

High-fat diet-induced changes in body mass and hypothalamic gene expression in wild-type and leptin-deficient mice

We tested whether diet-induced obesity results from increased energy consumption, is associated with changes in expression of genes involved in leptin signal transduction, and is altered by hyperleptinemia. C57BL/6 mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for up to 15 weeks. HFD mice weighed significantly more than LFD controls by 3 weeks, despite consuming less energy. HFD mice had significantly greater leptin, insulin, and glucose levels than LFD mice, suggesting leptin and insulin resistance. Adiponectin levels declined with age but were unaffected by diet. HFD was associated with altered hypothalamic expression of genes whose products regulate the activity or nuclear translocation of STAT3, an important mediator of leptin actions. Expression of two isoforms of the leptin receptor decreased at 15 weeks in hypothalami of HFD mice in a tissue-specific manner. The type of fat (saturated versus unsaturated) did not influence weight gain on an HFD, but animals on LFD gained significantly more weight and adiposity if the dietary fat consisted mostly of saturated fats; this occurred despite no difference in energy consumption or absorption. Replacement of leptin to leptin-deficient ob/ob mice decreased hypothalamic leptin receptor expression and did not prevent HFD-induced weight gain. It is concluded that (1) increased energy consumption is not required for HFD-induced obesity in C57BL/6 mice, (2) HFD results in weight gain partly by modulating hypothalamic leptin-signaling pathways, (3) saturated fats induce weight gain even when total fat content of the diet is low, and (4) the effects of HFD are manifest in the presence or absence of circulating leptin.     

Macrophage scavenger receptor (SR-A I/II) deficiency reduced diet-induced atherosclerosis in C57BL/6J mice.

The effects of SR-A I/II deficiency and a synthetic anti-oxidant BO-653 on a diet-induced atherosclerosis in C57BL/6J, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, were examined. Quantitative analysis of the extent of atherosclerotic lesions in the mice fed the high-fat diet revealed that the atherosclerotic lesion area in SR-A I/II mutants was significantly reduced by 70% compared to wild type mice. A similar level of lesion reduction (75%) was found in wild type mice fed the high-fat diet supplemented with 0.6% BO-653 compared to those without BO-653. Thus, for C57BL/6J in the setting of prolonged exposure to a high-fat diet, defect of SR-A I/II expression is significantly protective against the development of atherosclerosis, as is the synthetic anti-oxidant BO-653. These results indicate that SR-A I/II has a crucial role in atherosclerotic lesion formation with uptake of oxidized-LDL in this mouse model.     

No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychotic drugs

RATIONALE: Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6J mice. The effect of dietary fat on weight gain and serum lipids in this model is unknown. OBJECTIVES: Test the hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet. METHODS: Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either a low-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition, and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, and risperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in change were analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI and FE were compared using two-way ANOVA. RESULTS: AAD-treated mice gained significantly more weight than controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time (P<0.001). AAD-treated mice had significantly higher FE than controls (P<0.05); however, there was no significant drug by diet interaction (P=0.65). Risperidone low-fat mice gained significantly more absolute fat mass than placebo low-fat mice (P<0.05). All treatment groups, except quetiapine low-fat and olanzapine high-fat, gained significantly more absolute lean mass than placebo controls (P<0.05). Cholesterol levels were significantly lower in quetiapine and risperidone than placebo (P<0.05). Risperidone low-fat mice had significantly higher triglyceride levels than placebo and risperidone high-fat mice (P<0.05). CONCLUSIONS: A high-fat diet does not increase AAD-induced BW gain in female mice during a 3-week treatment period.     

Neuroendocrine characterization and anorexigenic effects of telmisartan in diet- and glitazone-induced weight gain

Telmisartan is an angiotensin II receptor blocker with peroxisome proliferator-activated receptor-γ agonistic properties. Telmisartan prevents weight gain and decreases food intake in models of obesity and in glitazone-treated rodents. This study further investigates the influence of telmisartan and pioglitazone and their association on weight gain and body composition by examining their influence on neuroendocrine mediators involved in food intake. Male C57/Black 6 mice were fed a high-fat diet, weight matched, and randomized in 4 treatment groups: vehicle, pioglitazone, telmisartan, and pioglitazone-telmisartan. Weight gain, food and water intake, body composition, plasma leptin levels, and the hypothalamic expression of neuroendocrine mediators were analyzed. Additional studies were performed with irbesartan and in angiotensin II 1_A receptor-knockout mice. Telmisartan abolished weight and fat gain in vehicle- and pioglitazone-treated mice while decreasing food intake, the hypothalamic expression of the agouti-related protein, and plasma leptin levels. Modifications in neuropeptide Y and proopiomelanocortin were not consistent with changes in food intake. The effects on weight gain and expression of the agouti-related protein were intermediate with irbesartan. The effects of telmisartan on weight gain were even more pronounced in angiotensin II 1_A receptor-knockout mice. This study confirms the anorexigenic effects of telmisartan in mice fed a high-fat diet and suggests for the first time a functional role of telmisartan on hypothalamic orexigenic agouti-related protein regulation. These anorexigenic properties abolish both weight gain and body composition modifications in fat-fed and glitazone-treated mice. The anorexigenic properties are independent from the angiotensin II 1_A receptor.     

Analysis of the effect of leptin on immune function in vivo using diet-induced obese mice

Leptin can regulate several immune functions. However, the role of leptin on lymphocyte function has not been recognized in vivo. Accordingly, we have investigated the effect of leptin on starvation-induced immune dysfunction using diet-induced obese mice. To induce obesity, C57BL/6J mice were fed a high-fat diet for 14 weeks and control mice were fed a standard diet for the same period. The obese and control groups of mice were then starved for 48 h, and received intraperitoneal injections of recombinant leptin or phosphate-buffered saline four times during starvation. Other control mice in both diet groups were free fed without being starved. Although starvation of the control mice dramatically reduced the weights of the immune organs, cytokine production and increased proliferation of cultured splenocytes, these levels returned to those of the free-feeding groups with exogenous leptin administration. However, these effects of leptin were not observed in obese mice. These findings provide some evidence that leptin can regulate the immune function in vivo. It is also suggested that the action of leptin might not appear in obesity.