Diet-induced Obese Rodents Research Articles

Intermittent intraperitoneal infusion of peptide YY(3-36) reduces daily food intake and adiposity in obese rats

Peptide YY(3-36) [PYY(3-36)] is a gut-brain peptide that decreases food intake when administered by intravenous infusion to lean and obese humans and rats. However, chronic administration of PYY(3-36) by osmotic minipump to lean and obese rodents produces only a transient reduction in daily food intake and weight gain. It has recently been shown that 1-h intravenous infusions of PYY(3-36) every other hour for 10 days produced a sustained reduction in daily food intake, body weight, and adiposity in lean rats. Here, we determined whether intermittent delivery of PYY(3-36) can produce a similar response in diet-induced obese rats. During a 21-day period, obese rats (body fat >25%) received twice daily intraperitoneal infusion of vehicle (n = 18) or PYY(3-36) (n = 24) during hours 1-3 and 7-9 of the dark period. Rats had free access to both a 45% fat solid diet and a 29% fat liquid diet; intakes were determined from continuous computer recording of changes in food container weights. To sustain a 15-25% reduction in daily caloric intake, the initial PYY(3-36) dose of 30 pmol.kg(-1).min(-1) was reduced to 10 pmol.kg(-1).min(-1) on day 10 and then increased to 17 pmol.kg(-1).min(-1) on day 13. This dosing strategy produced a sustained reduction in daily caloric intake of 11-32% and prevented body weight gain (8 +/- 6 vs. 51 +/- 11 g) and fat deposition (4.4 +/- 7.6 vs. 41.0 +/- 12.8 g). These results indicate that intermittent intraperitoneal infusion of PYY(3-36) can produce a sustained reduction in food intake and adiposity in diet-induced obese rodents consuming palatable high-fat foods.

Telmisartan prevents the glitazone-induced weight gain without interfering with its insulin-sensitizing properties

Glitazones are peroxisome proliferator-activated receptor (PPAR)-gamma agonists with powerful insulin-sensitizing properties. They promote the development of metabolically active adipocytes that can lead to a substantial gain in fat mass. Telmisartan is an ANG II type 1 receptor antagonist with partial PPAR-gamma agonistic properties. Recently, telmisartan has been reported to prevent weight gain and improve insulin sensitivity in diet-induced obese rodents. The goal of this study was to examine the influence of telmisartan on pioglitazone-induced weight gain and insulin-sensitizing properties in the following two models of insulin resistance: a nongenetic model (high-fat-fed Sprague Dawley rats) and the genetically obese fa/fa Zucker rat. After a 4-wk treatment, the pioglitazone-induced increase in fat mass was modest in the Sprague Dawley rats and severe in the Zucker rats. In both models, these effects were substantially decreased by concomitant treatment with telmisartan. The effects of telmisartan on body weight and fat mass in the Zucker rats were abolished by pair feeding, suggesting that it is the result of a decrease in food intake. Telmisartan did not interfere with the insulin-sensitizing properties of pioglitazone. This study demonstrates that telmisartan attenuates the glitazone-induced increase in fat mass without interfering with its insulin-sensitizing properties.

Animal models of obesity

Background Obesity stems from a prolonged imbalance between the levels of energy intake and expenditure, with the resultant surplus being stored as body lipids. Our understanding of the regulation of food intake and the physiological basis of differences in energy expenditure is owed, in large part, to studies made on animals. Moreover, animal models have been a cornerstone of studies of environmental effects, such as epigenetics, responses to high-fat and low-calorie diets and the identification and development of pharmaceuticals for obesity treatment. This review provides some examples of the animal work that has been performed, and focuses on the variation in approaches that have been taken and their potential, rather than aiming to be a comprehensive summary.

6-(4-Chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-Based Melanin-Concentrating Hormone Receptor 1 Antagonist

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.

Bromocriptine reduces steatosis in obese rodent models

Obesity is a risk factor for glucose intolerance, steatosis, and oxidative stress, characteristics of nonalcoholic fatty liver disease. Bromocriptine may have anti-obesity, insulin-sensitizing, lipolytic, and antioxidant properties. We, therefore, hypothesized that bromocriptine would improve markers of nonalcoholic fatty liver disease in obese rodent models. We performed a randomized, controlled experiment in genetically obese fatty Zucker rats and diet-induced obese rats to assess for behavioral and peripheral anti-obesity actions of bromocriptine (10mg/kg) that would improve nonalcoholic fatty liver disease. Behaviorally, food intake decreased and locomotor activity increased in bromocriptine-treated fatty Zucker and dietary-induced obese rats. Peripherally, liver triglycerides were significantly reduced and hepatic manganese superoxide dismutase significantly increased in bromocriptine-treated fatty Zucker and diet-induced obese rats compared to controls. Blood glucose was significantly lower in bromocriptine-treated Zucker rats compared to fatty controls and was no different than that of lean controls. Improvements in obesigenic behaviors, glucose tolerance, hepatic lipid accumulation, and mitochondrial oxidative stress observed in genetically obese and diet-induced obese rodents indicate that bromocriptine may be promising as a broad-based therapy for nonalcoholic fatty liver disease.

Hypothalamic Phosphatidylinositol 3‐Kinase‐Phosphodiesterase 3B‐Cyclic AMP Pathway of Leptin Signalling is Impaired Following Chronic Central Leptin Infusion

Leptin signalling in the hypothalamus is critical for the maintenance of normal body weight. Although hyperleptinaemia in obese people suggests a state of leptin resistance, and diet-induced obesity in rodents is associated with central leptin resistance, the underlying mechanisms remain unclear. Recent evidence suggests that, in addition to the signal transducer and activator of the transcription-3 (STAT3) pathway, leptin action is critical for energy homeostasis through an insulin-like signalling pathway involving an increase in phosphatidylinositol 3-kinase (PI3K) and phosphodiesterase 3B (PDE3B) activities and reduction in cyclic AMP (cAMP) levels in the hypothalamus. Here, we show that chronic central leptin (160 ng/h) infusion, which resulted in the development of resistance to the satiety action of leptin, impaired the PI3K-PDE3B-cAMP pathway of leptin signalling in the hypothalamus in that PI3K and PDE3B activities were increased and cAMP levels were decreased in the hypothalamus on day 2 of leptin infusion but remained unchanged on day 16. Additionally, induction of tyrosyl phosphorylation of insulin receptor substrate-1 observed on day 2 was not evident on day 16 of leptin infusion. By contrast, signalling through the STAT3-pathway remained activated in the hypothalamus throughout 16 days of leptin infusion. These findings show a differential response in PI3K-PDE3B-cAMP (impaired) and STAT3 (up-regulated) pathways to chronic central leptin infusion, and suggest a selective resistance in the PI3K-PDE3B-cAMP pathway of leptin signalling following a chronic increase in hypothalamic leptin tone attained by central infusion of this peptide hormone.

418. rAAV-Mediated Expression of Adiponectin Receptor (AdipoR2) cDNA in Muscle Prevents the Development of Obesity in DIO Rats

The adiponectin (Acrp30) is a fat-derived hormone that acts as antidiabetic adipokine. Previously, it had been successfully used to prevent the development of obesity in rodent model (PNAS 2003, v.100, p.14217–14222). The adiponectin receptors, AdipoR1 and AdipoR2, are members of a novel, GPCR-like family of receptors that, upon activation by the ligand, stimulate fatty-acid oxidation and glucose uptake in the liver and muscle. In this study, we investigated the long-term effects of gene therapy of obesity by the adiponectin receptor AdipoR2 cDNA delivered via rAAV1 vector. The rate of body weight (BW) gain and insulin-enhancing effect were tested in diet-induced obese (DIO, Levin's rat) rodent model fed high fat (60%) diet. We have shown that single intramuscular injection of 6x10e12 physical particles of the vector resulted in sustained (up to 160 days) statistically significant (p=0.001) reduction in BW. Distribution of white fat was measured by MRI, intramyocellular (IMCLs) and hepatocellular (HepCLs) lipids composition were monitored by MRS. The endocrine status of the treated rats was assessed using simultaneous multi-analyte detection protocol (LUMINEX), while the ip Glucose Tolerance Test (GTT) was applied to measure the ability of treated rats to withstand glucose challenge. The molecular mechanisms of weight-maintenance resulted from AdipoR2 transgene expression were investigated by assaying downstream signal transduction pathways via AMPK and PPAR-alpha activation. Our data demonstrate the therapeutic physiological effect of the BW reduction mediated by the ectopic expression of adipokine receptor AdipoR2.

Selective Up-regulation of Fatty Acid Uptake by Adipocytes Characterizes Both Genetic and Diet-induced Obesity in Rodents

Long chain fatty acid transport is selectively up-regulated in adipocytes of Zucker fatty rats, diverting fatty acids from sites of oxidation toward storage in adipose tissue. To determine whether this is a general feature of obesity, we studied [(3)H]oleate uptake by adipocytes and hepatocytes from 1) homozygous male obese (ob), diabetic (db), fat (fat), and tubby (tub) mice and from 2) male Harlan Sprague-Dawley rats fed for 7 weeks a diet containing 55% of calories from fat. V(max) and K(m) were compared with controls of the appropriate background strain (C57BL/6J or C57BLKS) or diet (13% of calories from fat). V(max) for adipocyte fatty acid uptake was increased 5-6-fold in ob, db, fat, and tub mice versus controls (p < 0.001), whereas no differences were seen in the corresponding hepatocytes. Similar changes occurred in fat-fed rats. Of three membrane fatty acid transporters expressed in adipocytes, plasma membrane fatty acid-binding protein mRNA was increased 9-11-fold in ob and db, which lack a competent leptin/leptin receptor system, but was not increased in fat and tub, i.e. in strains with normal leptin signaling capability; fatty acid translocase mRNA was increased 2.2-6.5-fold in tub, ob, and fat adipocytes, but not in db adipocytes; and only marginal changes in fatty acid transport protein 1 mRNA were found in any of the mutant strains. Adipocyte fatty acid uptake is generally increased in murine obesity models, but up-regulation of individual transporters depends on the specific pathophysiology. Leptin may normally down-regulate expression of plasma membrane fatty acid binding protein.

Depressed expression of adipocyte beta-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents.

To determine whether the dramatic reduction in expression and functional activity of the beta3-adrenergic receptor (AR) and beta1AR subtypes originally observed in adipose tissue of the C57BL/6J Lep(ob)/Lep(ob) ('obese') mouse are general features of all models of obesity, and whether obesity-related differences in betaAR subtype expression occur between adipose depots. Survey of adipose tissue betaAR expression from four mouse models of congenital obesity: the 'obese' mouse (C57BL/6J Lep(ob)/Lep(ob)), the 'diabetic' mouse (C57BL/KsJ LepRdb/LepRdb), the 'tubby' mouse (C57BL/6J tub/tub) and the 'fat' mouse (C57BL/KsJ Cpe(fat)/Cpe(fat)), and in a model of high-fat diet-induced obesity in C57BL/6J mice. Expression of the betaAR subtypes was measured by Northern blot hybridization in white and brown adipose depots. In the severely obese Lep(ob) and LepRdb mice, mRNA concentrations of beta3AR and beta1AR in white adipose tissue (WAT) were decreased by > 99% and by > 70%, respectively. More modest effects on beta3AR expression were observed in brown adipose tissue (BAT, decreased by 20 - 30%). In less severe forms of obesity, as found in the tubby and carboxypeptidase (Cpe)fat mice, and in diet-induced obese B6 mice, beta3AR expression was decreased in WAT by up to 90%, with more modest decreases in interscapular BAT (IBAT). Changes in beta1AR mRNA concentrations were more variable. Beta2AR mRNA levels did not differ in most cases, with the exception that there was a 3-5-fold increase in BAT for both Lep(ob) and LepRdb mice. Impaired expression of adipocyte betaAR subtypes is a general feature of both genetic and dietary obesity in mice. The degree of obesity is correlated with the extent of loss of beta3AR and beta1AR expression in WAT. The distinct endocrine abnormalities associated with these obesity models may be responsible for the degree of impaired adipocyte betaAR expression.