The Novel Antiobesic HMR1426 Reduces Food Intake without Affecting Energy Expenditure in Rats

Objective: To determine the effect of acute and chronic administration of a new food intake‐reducing compound (HMR1426) with novel mode of action (retardation of gastric emptying) on body weight development, food intake, and energy metabolism in rats. Research Methods and Procedures: Adult male Shoe‐Wistar rats were implanted with transponders allowing registration of body temperature (T_b) and locomotor activity. HMR1426 (10 or 50 mg/kg) was given orally, and acute (8 hours) and chronic (15 days) effects were measured on food intake, T_b, activity, total energy expenditure (indirect calorimetry), and epididymal adipose tissue mass. The effect of chronic treatment was compared with the effect of sibutramine (10 mg/kg). Results: HMR1426 (50 mg/kg) caused an acute and chronic decrease of food intake. There was no effect on the level and daily pattern of total energy expenditure, T_b, and locomotor activity. Respiratory quotient was acutely decreased by HMR1426 due to reduced food intake. Chronic treatment with HMR1426 decreased weight gain by 31% and epididymal white fat by 24%. Sibutramine caused a respective reduction of 48% and 35%. Energy efficiency was not affected by HMR1426 in contrast to sibutramine, which reduced energy efficiency and transiently increased activity. Discussion: HMR1426 showed an anorectic potential in rats and decreased body weight and fat mass. This was achieved solely by reducing food intake without influencing overall energy expenditure or behavior suggesting a peripheral mode of action. Thus, HMR1426 can be considered a potential new drug for obesity treatment.     

Topiramate Reduces Energy and Fat Gains in Lean (Fa/?) and Obese (fa/fa) Zucker Rats

Objective: This study examined the effects of topiramate (TPM), a novel neurotherapeutic agent reported to reduce body weight in humans, on the components of energy balance in female Zucker rats. Research Methods and Procedures: A 2 × 3 factorial experiment was performed in which two cohorts of Zucker rats differing in their phenotype (phenotype: lean, Fa/?; obese, fa/fa) were each divided into three groups defined by the dose of TPM administered (dose: TPM 0, vehicle; TPM 15, 15 mg/kg; TPM 60, 60 mg/kg). Results: The reduction in body weight gain induced by TPM in both lean and obese rats reflected a decrease in total body energy gain, which was more evident in obese than in lean rats. Whereas TPM administration did not influence the intake of digestible energy in lean rats, it induced a reduction in food intake in obese animals. In lean, but not in obese rats, apparent energy expenditure (as calculated by the difference between energy intake and energy gain) was higher in rats treated with TPM than in animals administered the vehicle. The low dose of TPM decreased fat gain (with emphasis on subcutaneous fat) without affecting protein gain, whereas the high dose of the drug induced a reduction in both fat and protein gains. The effects of TPM on muscle and fat depot weights were representative of the global effects of TPM on whole body fat and protein gains. The calculated energetic efficiency (energy gain/energy intake) was decreased in both lean and obese rats after TPM treatment. TPM dose independently reduced hyperinsulinemia of obese rats, but it did not alter insulinemia of lean animals. Discussion: The present results provide sound evidence for the ability of TPM to reduce fat and energy gains through reducing energetic efficiency in both lean and obese Zucker rats.     

Effects of different intermittent peptide YY (3-36) dosing strategies on food intake, body weight, and adiposity in diet-induced obese rats

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces either no effect or a transient reduction in food intake and body weight. Our aim here was to identify an intermittent dosing strategy for intraperitoneal infusion of peptide YY(3-36) [PYY(3-36)] that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (665+/-10 g body wt, 166+/-7 g body fat) with intraperitoneal catheters tethered to infusion swivels had free access to a high-fat diet. Vehicle-treated rats (n=23) had relatively stable food intake, body weight, and adiposity during the 9-wk test period. None of 15 PYY(3-36) dosing regimens administered in succession to a second group of rats (n=22) produced a sustained 15-25% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 9-wk period by 12% (594+/-15 vs. 672+/-15 g) and 43% (96+/-7 vs. 169+/-9 g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was >or=3 h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was <3 h suggested possible receptor downregulation and tolerance to frequent PYY(3-36) administration; however, food intake significantly increased when PYY(3-36) treatments were discontinued for 1 day following apparent loss in treatment efficacies. Together, these results demonstrate the development of a potent homeostatic response to increase food intake when PYY(3-36) reduces food intake and energy reserves in diet-induced obese rats.     

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.     

Central leptin gene therapy blocks ovariectomy-induced adiposity

Objective: In this study, we tested the hypothesis that insufficiency of leptin restraint in the hypothalamus is responsible for promoting weight gain and adiposity after ovariectomy (ovx). Whether increasing leptin transgene expression can overcome the diminution in leptin restraint was evaluated in ovx rats. Research Methods and Procedures: Enhanced leptin or green fluorescent protein (GFP; control) transgene expression was induced by a single intracerebroventricular injection of recombinant adeno‐associated viral vector encoding either leptin gene (rAAV‐lep) or GFP gene (rAAV‐GFP; control) in acutely and chronically ovx rats. Body weight and food intake responses were monitored weekly. White adipose tissue (WAT) mass and serum levels of WAT‐derived hormones, leptin, and adiponectin were analyzed at termination of the experiments. Results and Discussion: An increase in leptin transgene expression in the hypothalamus initiated soon after ovx blocked hyperphagia and body weight gain and markedly suppressed WAT mass and adipokines, leptin, and adiponectin. Similar suppression of weight gain and adiposity and serum leptin and adiponectin levels after intracerebroventricular rAAV‐lep injection in chronically ovx rats were observed concomitant with unchanged daily food intake. These findings are consistent with the hypothesis that in the absence of ovarian steroids, the existent insufficiency of leptin restraint at the hypothalamic level can be overcome with ectopic leptin expression, thereby reinstating central control on weight and adiposity.     

Efficiency of intermittent exercise on adiposity and fatty liver in rats fed with high-fat diet

Objective: This study aimed to examine and compare the effects of continuous or intermittent exercises on adiposity and fatty liver in rats fed with high‐fat diet. Methods and Procedures: Wistar rats were divided according to diet composition—chow diet (C) or high‐fat diet (H)—and kinds of exercise—sedentary (S), continuous (CE), or intermittent (IE) exercises. The CE group swam 90 min/day, and the IE group swam 3 × 30 min/day (at 4‐h intervals between sessions); both groups exercised 5 days/week during 8 weeks. Body weight and food intake were recorded daily. Lipogenesis rate in vivo was determined by the incorporation of ³H₂O into saponified lipids in retroperitoneal (RET), epididymal (EPI), and visceral (VIS) white adipose tissues, brown adipose tissue (BAT), liver (L), and gastrocnemius muscle (GAST) using the gravimetric method. Total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, and triacylglycerol (TG) were analyzed. Results: The major finding of this study is that IE was more efficient than CE in reducing the adverse effects of high‐fat diet and sedentarism. There was an improvement in the lipid profile and a reduction in food intake, body weight gain, visceral and central adiposity, and fatty liver, contributing to the control of obesity and other comorbidities, including nonalcoholic fat liver diseases. Discussion: Earlier studies have discussed the effects of diet consumption on adiposity and their relation to chronic diseases and obesity. This study discusses the effects of high‐fat diet consumption and the different kinds of exercise on weight gain, adiposity, fatty liver, and lipid profile in rats. The results may depend on the exercise, time of each session, age, gender, and experimental period.     

Effects of intermittent intraperitoneal infusion of salmon calcitonin on food intake and adiposity in obese rats

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces no effect or a transient reduction in daily food intake and body weight. Our aim was to identify an intermittent dosing strategy for intraperitoneal infusion of salmon calcitonin (sCT), a homolog of amylin that produces a sustained 25-35% reduction in daily food intake and adiposity in diet-induced obese rats. Rats (649 +/- 10 g body wt, 27 +/- 1% body fat), with intraperitoneal catheters tethered to infusion swivels, had free access to a 45% fat diet. Food intake, body weight, and adiposity during the 7-wk test period were relatively stable in the vehicle-treated rats (n = 16). None of 10 sCT dosing regimens administered in succession to a second group of rats (n = 18) produced a sustained 25-35% reduction in daily food intake for >5 days, although body weight and adiposity were reduced by 9% (587 +/- 12 vs. 651 +/- 14 g) and 22% (20.6 +/- 1.2 vs. 26.5 +/- 1.1%), respectively, across the 7-wk period. The declining inhibitory effect of sCT on daily food intake with the 6-h interinfusion interval appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of sCT on daily food intake with the 2- to 3-h interinfusion interval suggested possible receptor downregulation and tolerance to frequent sCT administration; however, food intake increased dramatically when sCT was discontinued for 1 day after apparent loss of treatment efficacy. Together, these results demonstrate the activation of a potent homeostatic response to increase food intake when sCT reduces food intake and energy reserves in diet-induced obese rats.     

S 23521 Decreases Food Intake and Body Weight Gain in Diet‐Induced Obese Rats

Objective: To investigate the effect of S 23521, a new glucagon‐like peptide‐1‐(7‐36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis. Research Methods and Procedures: Lean and diet‐induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 μg/kg) or subcutaneously (100 μg/kg) for 14 and 20 days, respectively. Because the low‐dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end‐points. Results: Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle‐treated counterparts (3401 ± 65 vs. 3898 ± 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein‐1, uncoupling protein‐3, leptin, resistin, and peroxisome proliferator‐activated receptor (PPAR)‐γ were observed. Discussion: S 23521 is an effective glucagon‐like peptide‐1‐(7‐36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet‐induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.     

Lipoic acid prevents body weight gain induced by a high fat diet in rats: Effects on intestinal sugar transport

Several studies have suggested that oxidative stress might cause and aggravate the inflammatory state associated with obesity and could be the link between excessive weight gain and its related disorders such as insulin resistance and cardiovascular diseases. Thus, antioxidant treatment has been proposed as a therapy to prevent and manage obesity and associated complications. Therefore, the aim of the present study was to investigate the effects of supplementation of a standard or high fat diet with the antioxidant lipoic acid (LA) during 56 days, on body weight gain, adiposity, feed efficiency and intestinal sugar absorption, in male Wistar rats. LA supplementation induced a lower body weight gain and adipose tissue size in both control or high fat fed rats accompanied by a reduction in food intake. The group fed on a high fat diet and treated with LA (OLIP group) showed a lower body weight gain than its corresponding Pair-Fed (PF) group (P<0.05), which received the same amount of food than LA-treated animals but with no LA. In fact, LA induced a reduction on feed efficiency and also significantly decreased intestinal α-methylglucoside (α-MG) absorption both in lean and obese rats. These results suggest that the beneficial effects of dietary supplementation with LA on body weight gain are mediated, at least in part, by the reduction observed in food intake and feed efficiency. Furthemore, the inhibitory action of LA on intestinal sugar transport could explain in part the lower feed efficiency observed in LA-treated animals and therefore, highlighting the beneficial effects of LA on obesity.     

Altered Hypothalamic Signaling and Responses to Food Deprivation in Rats Fed a Low‐Carbohydrate Diet

Objective: To model how consuming a low‐carbohydrate (LC) diet influences food intake and body weight. Research Methods and Procedures: Food intake and body weight were monitored in rats with access to chow (CH), LC‐high‐fat (HF), or HF diets. After 8 weeks, rats received intracerebroventricular injections of a melanocortin agonist (melanotan‐II) and antagonist (SHU9119), and feeding responses were measured. At sacrifice, plasma hormones and hypothalamic expression of mRNA for proopiomelanocortin (POMC), melanocortin‐4 receptor, neuropeptide Y (NPY), and agouti related protein (AgRP) were assessed. A second set of rats had access to diet (chow or LC‐HF) for 4 weeks followed by 24 h food deprivation on two occasions, after which food intake and hypothalamic POMC, NPY, and AgRP mRNA expression were measured. Results: HF rats consumed more food and gained more weight than rats on CH or LC‐HF diets. Despite similar intakes and weight gains, LC‐HF rats had increased adiposity relative to CH rats. LC‐HF rats were more sensitive to melanotan‐II and less sensitive to SHU9119. LC‐HF rats had increased plasma leptin and ghrelin levels and decreased insulin levels, and patterns of NPY and POMC mRNA expression were consistent with those of food‐deprived rats. LC‐HF rats did not show rebound hyperphagia after food deprivation, and levels NPY, POMC, and AgRP mRNA expression were not affected by deprivation. Discussion: Our results demonstrate that an LC diet influences multiple systems involved in the controls of food intake and body weight. These data also suggest that maintenance on an LC‐HF diet affects food intake by reducing compensatory responses to food deprivation.     

Feeding and temperature responses to intravenous leptin infusion are differential predictors of obesity in rats

Obesity is frequently associated with leptin resistance. The present study investigated whether leptin resistance in rats is present before obesity develops, and thus could underlie obesity induced by 16 wk exposure to a liquid, palatable, high-energy diet (HED). Before HED exposure, male Wistar rats (weighing between 330 and 360 g) received intravenous infusions of 20 microg leptin 2 h before dark (approximately 57 microg/kg rat). Relative to saline infusion, this caused a highly variable effect on food intake (ranging between -94 and +129%), with food intake suppression that appeared negatively correlated with HED-induced increases in body weight gain, caloric intake, adiposity, and plasma leptin levels. In contrast, leptin's thermogenic response was positively correlated to body weight gain linked to weights of viscera, but not to adiposity. Before HED exposure, leptin unexpectedly increased food intake in some rats (fi+, n = 8), whereas others displayed the normal reduction in food intake (fi-, n = 7). HED-exposed fi+ rats had higher plasma leptin levels, retroperitoneal fat pad weight, HED intake, and body weight gain than fi- and chow-fed rats. These parameters were also higher in HED-exposed fi-rats relative to chow rats, except for plasma leptin concentrations. It is concluded that leptin's reduced efficacy to suppress food intake could predict obesity on an HED. An unexpected orexigenic effect of leptin might potentially contribute to this as well.     

Adult Female Rats Defend “Appropriate” Energy Intake after Adaptation to Dietary Energy

Objective: To determine if adult female rats adapt to lower and higher dietary energy density. Research Methods and Procedures: Study 1 compared high‐fat (56%), high‐energy density (HD) (21.6 kJ/g) and high‐fat (56%), low‐energy density (LD) (16.0 kJ/g) diets before surgery (two groups, 2 weeks, n = 16) and after surgery [ovariectomy (O) Sham (S); 2 × 2 factorial, n = 8; 6 weeks]. The second study (no surgery) compared high‐fat (60.0%), high‐energy (22.0 kJ/g) and low‐fat (10.0%), low‐energy (15.1 kJ/g) diets (n = 8). Results: In study 1, food intake was similar for the first 2 weeks, but rats on the LD diet consumed less energy, gained less weight, and had lower nonfasted serum leptin (all p < 0.0001) than rats on the HD diet. After surgery, rats on the LD and HD diets had similar weight gain, but rats on the LD diet consumed more food (p < 0.0001) and less energy (p < 0.009). O rats consumed more food and gained more weight (p < 0.0001) than S rats. Results from study 2 were similar to those from study 1. Discussion: The results demonstrated that O and S surgery rats and rats with no surgery adjust their food intake to defend a level of energy intake. This defense only occurred after a 2‐week adaptation period. The major differences in final body weights and abdominal fat resulted from the initial 2 weeks before adaptation to energy density. Rats fed higher‐energy diets seemed to “settle” at a higher level of adiposity, and rats fed lower‐energy diets consumed more food to increase energy consumption.     

Oligofructose Promotes Satiety in Rats Fed a High‐Fat Diet: Involvement of Glucagon‐Like Peptide‐1

Objective: To analyze the putative interest of oligofructose (OFS) in the modulation of food intake after high‐fat diet in rats and to question the relevance of the expression and secretion of intestinal peptides in that context. Research Methods and Procedures: Male Wistar rats were pretreated with standard diet or OFS‐enriched (10%) standard diet for 35 days followed by 15 days of high‐fat diet enriched or not with OFS (10%) treatment. Body weight, food intake, triglycerides, and plasma ghrelin levels were monitored during the treatment. On day 50, rats were food‐deprived 8 hours and anesthetized for blood and intestinal tissue sampling for further proglucagon mRNA, glucagon‐like peptide (GLP)‐1, and GLP‐2 quantification. Results: The addition of OFS in the diet protects against the promotion of energy intake, body weight gain, fat mass development, and serum triglyceride accumulation induced by a high‐fat diet. OFS fermentation leads to an increase in proglucagon mRNA in the cecum and the colon and in GLP‐1 and GLP‐2 contents in the proximal colon, with consequences on the portal concentration of GLP‐1 (increase). A lower ghrelin level is observed only when OFS is added to the standard diet of rats. Discussion: In rats exposed to high‐fat diet, OFS is, thus, able to modulate endogenous production of gut peptides involved in appetite and body weight regulation. Because several approaches are currently used to treat type 2 diabetes and obesity with limited effectiveness, dietary fibers such as OFS, which promote the endogenous production of gut peptides like GLP‐1, could be proposed as interesting nutrients to consider in the management of fat intake and associated metabolic disorders.     

Strain differences in the dose-response curves of adrenalectomized, starved-refed rats to dehydroepiandrosterone (DHEA)

The effects of adrenalectomy and dehydroepiandrosterone (DHEA) doses (0, 15, 30, 60, 120 and 240 mg/kg/day ip) on hepatic enzyme activity and lipid content and on the amount of epididymal fat pad lipid were studied in starved-refed BHE and Sprague-Dawley rats. BHE rats had significantly greater relative liver size, glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme (ME) activities, and percentage liver lipid but less epididymal fat pad lipid than Sprague-Dawley rats. Adrenalectomized (ADX) rats consumed significantly less food, gained less weight per day, and had less lipid in their livers and fat pads than intact rats. As the level of DHEA increased from 0 to 240 mg/kg/day there was a significant linear decrease in average daily weight gain, food intake, G6PD activity, and percentage liver lipid. At the 15 mg/kg/day dose, G6PD activity was significantly reduced without reductions in the other parameters measured. At the 120 mg/kg/day dose, however, weight gain, food intake, G6PD activity, and percentage liver lipid were significantly lower than that of the controls. At this dose DHEA treatment reduced food intake by 17% whereas it diminished average daily weight gain and G6PD activity by 30 and 56%, respectively. The 240 mg/kg/day dose of DHEA significantly reduced food intake, weight gain, liver lipid, G6PD activity, and ME activity. Intact and ADX BHE rats reduced their G6PD activity and liver lipid more rapidly than Sprague-Dawley rats as the level of DHEA administered increased. ADX Sprague-Dawley rats receiving DHEA had greater liver lipid content and enzyme activity than their intact counterparts whereas the reverse situation was true in BHE rats. These data indicate that the effect of DHEA on body weight gain, food intake, and hepatic and peripheral adiposity are dependent on the strain of rat, the adrenal status, and the DHEA dose.     

Dietary whey protein decreases food intake and body fat in rats

We investigated the effects of dietary whey protein on food intake, body fat, and body weight gain in rats. Adult (11-12 week) male Sprague-Dawley rats were divided into three dietary treatment groups for a 10-week study: control. Whey protein (HP-W), or high-protein content control (HP-S). Albumin was used as the basic protein source for all three diets. HP-W and HP-S diets contained an additional 24% (wt/wt) whey or isoflavone-free soy protein, respectively. Food intake, body weight, body fat, respiratory quotient (RQ), plasma cholecystokinin (CCK), glucagon like peptide-1 (GLP-1), peptide YY (PYY), and leptin were measured during and/or at the end of the study. The results showed that body fat and body weight gain were lower (P < 0.05) at the end of study in rats fed HP-W or HP-S vs. control diet. The cumulative food intake measured over the 10-week study period was lower in the HP-W vs. control and HP-S groups (P < 0.01). Further, HP-W fed rats exhibited lower N(2) free RQ values than did control and HP-S groups (P < 0.01). Plasma concentrations of total GLP-1 were higher in HP-W and HP-S vs. control group (P < 0.05), whereas plasma CCK, PYY, and leptin did not differ among the three groups. In conclusion, although dietary HP-W and HP-S each decrease body fat accumulation and body weight gain, the mechanism(s) involved appear to be different. HP-S fed rats exhibit increased fat oxidation, whereas HP-W fed rats show decreased food intake and increased fat oxidation, which may contribute to the effects of whey protein on body fat.     

Polymyxin B and Related Cyclic Peptides Facilitate Leanness and Reduce Fat Mass and Triglyceride Content in Ageing Rats: Potential Prototype Drugs Against Obesity

Polymyxin B (PMXB) blocks the action of insulin on glucose uptake in vitro. In vivo, it reverses hypoglycemia induced by exogenous insulin. Here we have treated mature male rats daily with PMXB over a period of two weeks. This therapy has decreased body weight by 11%, adipose fat mass by 46% and triglyceride levels by 39%, with no indication of liver or kidney toxicity. Two suboptimal parameters, however, were a decrease in food intake in the first week of treatment and some increase in fasting glucose levels. We have screened for PMXB-analogs having less associating affinity with rat-muscle phospholipids, and revealed that the same therapy using PMXB-derived peptide (nona-PMXB) is most optimal. This PMXB-analog is devoid of antibacterial activity and is four times less toxic than PMXB. Nona-PMXB therapy lower by 10, 32, 35 and 6% body weight gain, fat mass, circulating triglycerides and fasting glucose levels, respectively, in spite of normal or even elevated food intake in nona-PMXB treated rats. In summary, we found that nona-PMXB therapy is capable if inducing leanness in mature rats, particularly at the expense of decreasing fat-mass in adipose tissue. By and large, we suggest that lowering the action of insulin, on fat build-up solely, may be a therapeutically feasible task to fight with human adiposity in the future.     

Chronic treatment with olanzapine via a novel infusion pump induces adiposity in male rats

AimsClinical use of olanzapine has been suggested to be associated with weight gain and adiposity in schizophrenic patients. While studies in experimental animals have noted weight gain in olanzapine-treated female rats, these findings have yet to be replicated in males. This study investigated the effect of chronic subcutaneous infusion of olanzapine in male rats via a recently developed electrical microinfusion pump.Main methodsAn electrical microinfusion pump was subcutaneously implanted in male Sprague–Dawley rats who were then chronically administered olanzapine. Plasma olanzapine concentration and body weight were monitored, and fat pads were weighed after six weeks' olanzapine treatment.Key findingsPlasma olanzapine concentration plateaued within 4 h of commencement of chronic olanzapine 1.5 mg/animal/day infusion and remained constant until day 21. Six-week infusion of olanzapine at 1.5 but not 1 mg/animal/day induced significant adiposity in subcutaneous, epididymal, and retroperitoneal fat. Body weight and food intake values did not differ between olanzapine- and vehicle-treated rats throughout the experiment.SignificanceThe present study demonstrated that chronic infusion of olanzapine induced adiposity in male rats without inducing weight gain or hyperphagia, even with sufficient plasma concentration. This report is the first to provide information about adiposity-inducible plasma concentration of olanzapine in male rats.     

Both Maternal Over- and Undernutrition During Gestation Increase the Adiposity of Young Adult Progeny in Rats

FIOROTTO, MARTA L, TERESA A DAVIS, PATRICIA SCHOKNECHT, HARRY J MERSMANN AND WILSON G POND. Both maternal over- and undernutrition during gestation increase the adiposity of young adult progeny in rats. ObesRes. 1995;3:131–141. We examined the influence of maternal diet during gestation on the growth and body composition of the progeny. On day 1 of gestation, rat dams were assigned to one of four feeding regimens: free access to standard rodent chow throughout gestation (AL); 20 g feed/day (prebreeding intake) throughout gestation (PB); 10 g feed/day from day 1 to day 14, then ad libitum from day 15 to parturition (RAL); 10 g feed/day from day 1 to 14, then 20 g/day to parturition (RPB). Progeny were fed ad libitum on standard chow diet from 3 to 12 weeks of age; food intake and weight gain were measured over this time. Body composition was measured at 12 weeks. The PB regimen restricted maternal food intake during the third trimester only; the RAL regimen restricted intake by 50% for two trimesters and produced hyperphagia in the third; the RPB regimen restricted intake by 50% for two trimesters, then intake (per unit body weight) was similar to that of AL dams during the third trimester. Litter size and progeny birth, weaning, and 12-week body weights were similar among the four groups. At 12 weeks of age, PB progeny had the highest body fat (per kg fat-free mass), despite similar feed intake during the 9-week postweaning period. The increased fat was proportionally distributed among intra-abdominal and subcutaneous depots. Progeny of RAL, AL, and RPB dams had similar amounts of body fat, but in RAL progeny more fat was present in intra-abdominal depots. The weights of fat-free mass, gastrointestinal tract and hindlimb skeletal muscles were unaffected by maternal diet Restriction of maternal feed intake during the third week of gestation had subtle effects on the body composition of young adult progeny that could not be explained on the basis of differences in postweaning voluntary feed intake.     

Changes in leptin levels during lactation: implications for lactational hyperphagia and anovulation

In these studies we investigated the time course of changes in circulating leptin levels in lactating rats and the dependence of these changes on the energetic cost of lactation and evaluated the contribution of changes in leptin levels to lactational hyperphagia and infertility. In the first experiment, plasma leptin levels were measured on Days 5, 10, 15, 20, and 25 postpartum in freefeeding lactating rats and age-matched virgin females. Retroperitoneal and parametrial fat pads weights were obtained from the same females. In the second experiment the same measures, together with plasma insulin and prolactin levels, were taken on Days 15 and 20 postpartum from galactophore-cut and sham-operated females. In Experiments 3 and 4, the effects of exogenous leptin administration, either subcutaneously (sc) or intracerebroventricularly (icv), on lactational anovulation, maternal food intake, and dam and litter weights were examined. Circulating leptin levels decreased in lactating rats. Leptin levels were highly positively correlated with fat pad weight. Eliminating the energetic costs of lactation by preventing milk delivery induced dramatic increases in plasma leptin and insulin levels and also increased adiposity. Exogenous leptin administration did not affect length of lactational anovulation but reduced food intake, maternal body weight, and litter weight gain when given centrally and maternal body weight when given systemically. Together, these data show that the energetic costs of lactation are associated with a fall in circulating leptin levels but that these do not make a major contribution to the suppression of reproduction in lactating rats; however, they may be permissive to the hyperphagia of lactation.     

Chronic exercise lowers the defended body weight gain and adiposity in diet-induced obese rats

The effects of running wheel exercise and caloric restriction on the regulation of body weight, adiposity, and hypothalamic neuropeptide expression were compared in diet-induced obese male rats over 6 wk. Compared with sedentary controls, exercising rats had reduced body weight gain (24%), visceral (4 fat pads; 36%) and carcass (leptin; 35%) adiposity but not insulin levels. Hypothalamic arcuate nucleus (ARC) proopiomelanocortin (POMC) mRNA expression was 25% lower, but ARC neuropeptide Y (NPY), agouti- related peptide, dorsomedial nucleus (DMN) NPY, and paraventricular nucleus (PVN) corticotropin- releasing hormone (CRH) expression was comparable to controls. Sedentary rats calorically restricted to 85% of control body weight reduced their visceral adiposity (24%), leptin (64%), and insulin (21%) levels. ARC NPY (23%) and DMN NPY (60%) were increased, while ARC POMC (40%) and PVN CRH (14%) were decreased. Calorically restricted exercising rats an half as much as ad libitum-fed exercising rats and had less visceral obesity than comparably restricted sedentary rats. When sedentary restricted rats were refed after 4 wk, they increased intake and regained the weight gain and adiposity of sedentary controls. While refed exercising rats and sedentary rats ate comparable amounts, refed exercising rats regained weight and adiposity only to the level of ad libitum-fed exercising rats. Thus exercise lowers the defended level of weight gain and adiposity without a compensatory increase in intake and with a very different profile of hypothalamic neuropeptide expression from calorically restricted rats. This may be due to exercise-related factors other than plasma insulin and leptin.