Whey Protein Reduces Early Life Weight Gain in Mice Fed a High-Fat Diet

An increasing number of studies indicate that dairy products, including whey protein, alleviate several disorders of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in mice fed a high-fat diet hypothesising that the metabolic effects of whey would be associated with changes in the gut microbiota composition. Five-week-old male C57BL/6 mice were fed a high-fat diet ad libitum for 14 weeks with the protein source being either whey or casein. Faeces were collected at week 0, 7, and 13 and the fecal microbiota was analysed by denaturing gradient gel electrophoresis analyses of PCR-derived 16S rRNA gene (V3-region) amplicons. At the end of the study, plasma samples were collected and assayed for glucose, insulin and lipids. Whey significantly reduced body weight gain during the first four weeks of the study compared with casein (P<0.001–0.05). Hereafter weight gain was similar resulting in a 15% lower final body weight in the whey group relative to casein (34.0±1.0 g vs. 40.2±1.3 g, P<0.001). Food intake was unaffected by protein source throughout the study period. Fasting insulin was lower in the whey group (P<0.01) and glucose clearance was improved after an oral glucose challenge (P<0.05). Plasma cholesterol was lowered by whey compared to casein (P<0.001). The composition of the fecal microbiota differed between high- and low-fat groups at 13 weeks (P<0.05) whereas no difference was seen between whey and casein. In conclusion, whey initially reduced weight gain in young C57BL/6 mice fed a high-fat diet compared to casein. Although the effect on weight gain ceased, whey alleviated glucose intolerance, improved insulin sensitivity and reduced plasma cholesterol. These findings could not be explained by changes in food intake or gut microbiota composition. Further studies are needed to clarify the mechanisms behind the metabolic effects of whey.     

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.     

硫胺素、核黄素和烟酰胺对大鼠体重增长及脂代谢影响的实验研究

目的：B族维生素以辅酶的形式参与糖、脂肪和蛋白质代谢,本文观察硫胺素、核黄素和烟酰胺补充对高脂饲料诱导大鼠肥胖的影响。方法：采用预防肥胖模型法,2×2×2析因设计分为8组：高脂对照组（F0组）,高脂＋硫胺素（F1组）,高脂＋核黄素（F2组）,高脂＋烟酰胺（F3组）,高脂＋硫胺素＋核黄素（F4组）,高脂＋硫胺素＋烟酰胺（F5组）,高脂＋核黄素＋烟酰胺（F6组）,高脂＋硫胺素＋核黄素＋烟酰胺（F7组）,每组12只大鼠,给予高脂饲料喂养,同时硫胺素（100mg／kgbw／d）、核黄素（100mg／kgbw／d）、烟酰胺（250mg／kgbw／d）灌胃,另设正常对照组（C组）12只,普通饲料喂养,自来水灌胃,15周后,分析其体重、摄食量、体脂重量、血脂等实验前后的变化情况及各组动物之间的差别。结果：经过15周喂养后,高脂喂养大鼠体重比正常对照组平均增加了15．7％;而补充烟酰胺（F3）及联合硫胺素（F5）或核黄素（F6）以及三者联合补充（F7）组高脂喂养大鼠与高脂对照组（F0）相比,体重分别降低了35．0％,30．0％,30．1％和30．6％（P值均小于0．05）;甚至比正常对照组大鼠平均体重分别下降了22．8％,17．0％,17．0％和17．7％（P值均小于0．05）;而补充核黄素或和硫胺素组大鼠体重没有明显增加或降低（P值均大于0．05）。血脂分析结果显示高脂喂养并联合补充核黄素或／和烟酰胺和／或硫胺素组大鼠血清CHOL和LDL水平明显低于高脂对照组;而高脂喂养并联合补充烟酰胺（F3）及联合硫胺素（F5）或核黄素（F6）以及三者联合补充（F7）组大鼠LDL／HDL比值分别0．29、0．26、0．25和0．26,明显低于F0组的0．37（P值均小于0．05）。结论：大剂量烟酰胺可有效地调节血脂水平和控制肥胖大鼠的体重增长,而核黄素及硫胺素对控制肥胖     

硫胺素、核黄素和烟酰胺对大鼠体重增长及脂代谢影响的实验研究(英文)

目的:B族维生素以辅酶的形式参与糖、脂肪和蛋白质代谢,本文观察硫胺素、核黄素和烟酰胺补充对高脂饲料诱导大鼠肥胖的影响。方法:采用预防肥胖模型法,2×2×2析因设计分为8组:高脂对照组(F0组),高脂+硫胺素(F1组),高脂+核黄素(F2组),高脂+烟酰胺(F3组),高脂+硫胺素+核黄素(F4组),高脂+硫胺素+烟酰胺(F5组),高脂+核黄素+烟酰胺(F6组),高脂+硫胺素+核黄素+烟酰胺(F7组),每组12只大鼠,给予高脂饲料喂养,同时硫胺素(100 mg/kg bw/d)、核黄素(100mg/kg bw/d)、烟酰胺(250 mg/kg bw/d)灌胃,另设正常对照组(C组)12只,普通饲料喂养,自来水灌胃,15周后,分析其体重、摄食量、体脂重量、血脂等实验前后的变化情况及各组动物之间的差别。结果:经过15周喂养后,高脂喂养大鼠体重比正常对照组平均增加了15.7%;而补充烟酰胺(F3)及联合硫胺素(F5)或核黄素(F6)以及三者联合补充(F7)组高脂喂养大鼠与高脂对照组(F0)相比,体重分别降低了35.0%,30.0%,30.1%和30.6%(P值均小于0.05);甚至比正常对照组大鼠平均体重分别下降了22.8%,17.0%,17.0%和17.7%(P值均小于0.05);而补充核黄素或和硫胺素组大鼠体重没有明显增加或降低(P值均大于0.05)。血脂分析结果显示高脂喂养并联合补充核黄素或/和烟酰胺和/或硫胺素组大鼠血清CHOL和LDL水平明显低于高脂对照组;而高脂喂养并联合补充烟酰胺(F3)及联合硫胺素(F5)或核黄素(F6)以及三者联合补充(F7)组大鼠LDL/HDL比值分别0.29、0.26、0.25和0.26,明显低于F0组的0.37(P值均小于0.05)。结论:大剂量烟酰胺可有效地调节血脂水平和控制肥胖大鼠的体重增长,而核黄素及硫胺素对控制肥胖大鼠体重增长的作用不明显,尚待进一步研究;核黄素只能够降低血脂水平,提示大剂量烟酰胺可通过增加机体的能量代谢来控制体重的增长。     

Effect of Soy and Milk Whey Protein Isolates and Their Hydrolysates on Weight Reduction in Genetically Obese Mice

The effect on genetically obese mice of a milk whey protein isolate (WPI) and soy protein isolate (SPI) and their hydrolysates (WPI-H, SPI-H) on the rate of body fat disappearance was investigated. Male yellow KK mice were made obese by feeding with a high-fat diet containing 30% fat from 6 to 10 weeks of age. They were then fed with an energy-restricted low fat (5.0%) and high protein (35% WPI, WPI-H, SPI or SPI-H) diet for 2 weeks at the 60% level of energy intake by mice on laboratory feed. During the weight reduction period, the body weight of the WPI, WPI-H, SPI and SPI-H groups changed by -9.1, -9.1, -10.0 and -11.1 g/14 days, respectively, the reduction being significantly lower in the SPI-H group than in the WPI and WPI-H groups. The plasma total cholesterol level was significantly lower with the SPI diet, and the plasma glucose level was lower with the SPI and SPI-H diets than with the WPI and WPI-H diets. Although the body protein content was comparable in all the groups, the body fat content was significantly lower with the SPI diet than with the WPI diet, and was also significantly lower with the SPI-H diet than with the WPI and WPI-H diets. The weight of the perirenal fat pads was significantly lower with the SPI-H diet than with the WPI and WPI-H diets. These results indicate that SPI and SPI-H are suitable protein sources in an energy-restricted diet for treating obesity.     

LY226936 Administered Orally and Centrally to Obese Zucker Rats Suppresses Food Intake and Body Weight Gain

LY226936, methylcarbamothoic acid-S-(4,5-dihydro-2-thiazolyl) ester, is a new compound that, when administered to obese Zucker rats, caused reduced food intake. LY226936 reduced the food consumption after a single oral dose of 50 and 100 mg/kg. On chronic oral administration to meal-fed obese (5 to 35 mg/kg. once daily) and to fed obese and lean (15 mg/kg. twice daily) Zucker rats, LY226936 reduced food intake and body weight gain for periods ranging from 40 to 48 days. The effect on both parameters was statistically significant. There is no evidence in our studies that tolerance to the actions of LY226936 developed. LY226936 decreased the consumption of both high carbohydrate and high fat diets. Food consumption of meal-fed obese Zucker rats was reduced significantly each time a single dose of 10 ugm LY226936 per rat was infused intracerebroventricularly. None of the receptors studied (mu and kappa opioid, CCK, serotonin, neuropeptide Y, galinin, N-methyl-D-aspartic acid) appeared to bind LY226936 and therefore, appear not to be involved in the depression of food intake by the obese Zucker rat.     

Leucine and Protein Metabolism in Obese Zucker Rats

Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-¹⁴C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (∼300%), but lower plantaris and gastrocnemius masses (−21–24%). Plasma BCAAs and BCKAs were elevated 45–69% and ∼100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (−47–66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23–29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193–418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and protein turnover along with impaired BCKDC activity. Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation.     

A Surprising Link Between the Energetics of Ovariectomy‐induced Weight Gain and Mammary Tumor Progression in Obese Rats

Obesity increases the risk for postmenopausal breast cancer. We have modeled this metabolic context using female Wistar rats that differ in their polygenic predisposition for obesity under conditions of high‐fat feeding and limited physical activity. At 52 days of age, rats were injected with 1‐methyl‐1‐nitrosourea (MNU, 50 mg/kg) and placed in an obesogenic environment. At 19 weeks of age, the rats were separated into lean, mid‐weight, and obese rats, based upon their weight gained during this time. The rats were ovariectomized (OVX) at ～24 weeks of age and the change in tumor multiplicity and burden, weight gain, energy intake, tumor estrogen receptor (ER) status, and humoral metabolite and cytokine profiles were examined. The survival and growth of tumors increased in obese rats in response to OVX. OVX induced a high rate of weight gain during post‐OVX weeks 1–3, compared to SHAM‐operated controls. During this time, feed efficiency (mg gain/kcal intake) was lower in obese rats, and this reduced storage efficiency of ingested fuels predicted the OVX‐induced changes in tumor multiplicity (r = ?0.64, P < 0.001) and burden (r = ?0.57, P < 0.001). Tumors from obese rats contained more cells that expressed ERα, and post‐OVX plasma from rats with the lowest feed efficiency had lower interleukin (IL)‐2 and IL‐4 levels. Our observations suggest a novel link between obesity and mammary tumor promotion that involves impaired fuel metabolism during OVX‐induced weight gain. The metabolically inflexible state of obesity and its inability to appropriately respond to the OVX‐induced energy imbalance provides a plausible explanation for this relationship and the emergence of obesity's impact on breast cancer risk after menopause.     

Proteolytic Activity of Streptococcus bovis Cultured Alone or Associated with Prevotella albensis,on two kinds of Protein Substrates: Casein or Pea Proteins

This work aims at studying in detail, the interaction between two major bacterial species involved in the ruminal proteolysis, Streptococcus bovis and Prevotella albensis. We chose to investigate this interaction by examining their behaviour both alone in monoculture and together in co-culture on two kinds of protein substrates. Comparison of the behaviour of S. bovis and P. albensis in monoculture, in terms of growth and total proteolytic activity with protein as the sole source of nitrogen, showed that S. bovis grew more rapidly and developed a higher total proteolytic activity. A higher proportion of short peptides was generated at the end of the exponential growth phase on pea protein medium whereas peptide accumulation did not appear on casein medium for both species; peptides of casein origin would be used more by species in monoculture than those of pea origin. S. bovis predominated in number in both co-cultures but the balance between species was greater on pea proteins (S. bovis: 64% and P. albensis: 36%) than on casein (S. bovis: 86% and P. albensis: 14%). At the same time, the decrease of the proteolytic activity was smaller on pea protein medium than that with casein and the use of proteolysis products was facilitated; peptides liberated by pea protein hydrolysis accumulated less than those obtained from casein. Moreover, the diversity of the endopeptidases expressed increased on pea proteins and the exopeptidase activities remained rather constant whereas they were highly stimulated on casein medium. All the results obtained in co-culture on pea proteins allowed us to suggest that a greater synergism occurred between the two species for the breakdown of proteins.     

Retrograde Gastric Electrical Stimulation Reduces Food Intake and Weight in Obese Rats

Objective: To investigate the therapeutic potential of retrograde gastric electrical stimulation (RGES) for obesity in a rodent model of obesity. Research Methods and Procedures: The study was performed in 12 obese Zucker rats implanted with two pairs of gastric serosal electrodes, one pair for stimulation and the other for recording intrinsic gastric myoelectrical activity. It was composed of an acute study in three sessions to study the effect of RGES on intrinsic gastric myoelectrical activity and acute food intake and a chronic phase to study the short‐term effect of RGES on weight. RGES was performed through the distal stomach using long pulses at a frequency of tachygastria (known to induce gastric hypomotility). Results: RGES completely entrained intrinsic gastric myoelectrical activity and turned it into tachygastria at a certain strength. RGES reduced acute food intake compared with the control (p < 0.01). A 2‐week treatment of RGES resulted in a significant reduction in food intake (p = 0.002) and a significantly greater weight loss than sham stimulation (p = 0.004). Discussion: RGES at a tachygastrial frequency reduces food intake and results in weight loss in obese Zucker rats, and its effect is probably attributed to the introduction of tachygastria in the stomach.     

Calcium and Dairy Acceleration of Weight and Fat Loss during Energy Restriction in Obese Adults

Objective: Increasing 1, 25‐dihydroxyvitamin D in response to low‐calcium diets stimulates adipocyte Ca²⁺ influx and, as a consequence, stimulates lipogenesis, suppresses lipolysis, and increases lipid accumulation, whereas increasing dietary calcium inhibits these effects and markedly accelerates fat loss in mice subjected to caloric restriction. Our objective was to determine the effects of increasing dietary calcium in the face of caloric restriction in humans. Research Methods and Procedures: We performed a randomized, placebo‐controlled trial in 32 obese adults. Patients were maintained for 24 weeks on balanced deficit diets (500 kcal/d deficit) and randomized to a standard diet (400 to 500 mg of dietary calcium/d supplemented with placebo), a high‐calcium diet (standard diet supplemented with 800 mg of calcium/d), or high‐dairy diet (1200 to 1300 mg of dietary calcium/d supplemented with placebo). Results: Patients assigned to the standard diet lost 6.4 ± 2.5% of their body weight, which was increased by 26% (to 8.6 ± 1.1%) on the high‐calcium diet and 70% (to 10.9 ± 1.6% of body weight) on the high‐dairy diet (p < 0.01). Fat loss was similarly augmented by the high‐calcium and high‐dairy diets, by 38% and 64%, respectively (p < 0.01). Moreover, fat loss from the trunk region represented 19.0 ± 7.9% of total fat loss on the low‐calcium diet, and this fraction was increased to 50.1 ± 6.4% and 66.2 ± 3.0% on the high‐calcium and high‐dairy diets, respectively (p < 0.001). Discussion: Increasing dietary calcium significantly augmented weight and fat loss secondary to caloric restriction and increased the percentage of fat lost from the trunk region, whereas dairy products exerted a substantially greater effect.     

高乳清蛋白的肠内营养对大鼠伤口愈合的影响

探讨高乳清蛋白的肠内营养对大鼠创伤皮肤的促愈合作用.将36只SD大鼠随机分为3组,每组12只,即高乳清蛋白肠内营养组(A)、普通肠内营养组(B)、空白对照组(C),建立大鼠皮肤创伤模型后进行肠内营养支持,肠内营养用量为每天731.5kJ·kg-1,以灌胃的方式提供,分别于术后第7、14天测定血清蛋白、血红蛋白含量并计算创面愈合率.结果显示,术后第7、14天A组的血清蛋白、血红蛋白及伤口皮肤平均愈合率显著高于B、C组,差异具有统计学意义(p＜0.05).表明高乳清蛋白肠内营养具有较好的促进伤口愈合的作用.     

Time-Dependent Effects of Progressive Gamma -Linolenate Feeding on Hyperphagia,Weight Gain,and Erythrocyte Fatty Acid Composition During Growth of Zucker Obese Rats

Obese Zucker rats (fa/fa) have low levels of arachidonic acid (AA) in liver phospholipids (PL). We have previously shown that a 70% gamma-linolenate concentrate (GLA; an AA intermediate) fed at a fixed dose (0.07 g/day) normalized hepatic PL AA and reduced weight gain selectively in the obese animals. In a follow-up study, 16 obese (fa/fa) and 16 lean (Fa/Fa) 4-week-old male rats were randomized into 4 groups of 8 each and gavaged daily with soybean oil (SOY) containing 55% 18:2ω6 (an AA precursor) or GLA, using a progressive dose (≤ 5% of total calories) based on body weight. A defined diet with 11% of energy as SOY was fed ad libitum for 60 days. GLA obese had lower body weight (p<0.0001) and 60-day cumulative food intake (p<0.05) compared to SOY obese, but neither parameter differed between the lean groups. For the last twenty days cumulative food intake was identical for GLA obese and SOY lean, whereas SOY obese consumed 18% more (p<0.05). Thus the progressive dose of GLA selectively suppressed hyperphagia in obese Zucker rats. Erythrocytes collected at 15-day intervals showed parallel increases in AA in both genotypes over time, suggesting normal AA availability during rapid growth. Thus, the reduced PL AA in the livers from the obese rats probably reflects impaired distribution in selected tissues rather than reduced hepatic production. Due to the potential health risks of enriching tissue lipids with AA, great caution is advised in considering GLA as therapy for human obesity.     

Effect of Age on Protein Conservation during Very-Low-Energy Diet in Obese Sprague-Dawley Rats

JOHNSON, JULIA A, CHOON-HIE YU, MEI-UIH YANG, F. XAVIER PI-SUNYER. Effect of age on protein conservation during very-low-energy diet in obese Sprague-Dawley rats. Obes. Res. 1998;6:448-157. Objective : To examine the effect of age on body protein losses occurring during severe energy restriction in obesity. Research Methods and Procedures : Weanling (young) Sprague-Dawley rats (YR) were fed a high fat (35% energy) diet (HFD) until mean body weight approached that of a group of chowfed retired breeder (aged) rats (AR). Both groups were then fed HFD for an additional 2 weeks, after which selected controls from YR and AR groups were killed for baseline carcass analysis. Remaining rats were fed a very-low-energy diet (VLED, 33% kcal of HFD) for 3 weeks and then killed for carcass analysis. Results : YR had greater fat stores before VLED, and lost proportionately more fat and less protein during VLED than did AR. Weight loss composition during VLED was 66.7% fat, 11.1% protein, and 22.2% water in YR, and 39.4% fat, 26.2% protein, and 34.3% water in AR. Greater YR fat loss during VLED* (70.6 ± 30.4 vs. 32.6 ± 29.1 g in AR; mean ± SD) was paralleled by significantly larger decreases in epididymal and retroperitoneal fat pad weights, mean adipocyte size, and lipoprotein lipase activity. Greater protein loss in AR (21.6 ± 13.9 g vs. 11.8 ± 10.7 g in YR) coincided with larger decreases in visceral organ weights and serum thyroxine and triiodothyronine. Energy expenditure changes during VLED were similar between groups. Discussion : Dietary obese young rats appear better able than aged rats to conserve body protein while losing body fat during severe energy restriction.     

Exercise Training and Weight Gain in Obese Pregnant Women: A Randomized Controlled Trial (ETIP Trial)

BackgroundThe effectiveness of exercise training for preventing excessive gestational weight gain (GWG) and gestational diabetes mellitus (GDM) is still uncertain. As maternal obesity is associated with both GWG and GDM, there is a special need to assess whether prenatal exercise training programs provided to obese women reduce the risk of adverse pregnancy outcomes. Our primary aim was to assess whether regular supervised exercise training in pregnancy could reduce GWG in women with prepregnancy overweight/obesity. Secondary aims were to examine the effects of exercise in pregnancy on 30 outcomes including GDM incidence, blood pressure, blood measurements, skinfold thickness, and body composition.ConclusionsIn this trial we did not observe a reduction in GWG among overweight/obese women who received a supervised exercise training program during their pregnancy. The incidence of GDM in late pregnancy seemed to be lower in the women randomized to exercise training than in the women receiving standard maternity care only. Systolic blood pressure in late pregnancy was also apparently lower in the exercise group than in the control group. These results indicate that supervised exercise training might be beneficial as a part of standard pregnancy care for overweight/obese women.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01243554","term_id":"NCT01243554"}}NCT01243554     

Effects of Exendin‐4 Alone and With Peptide YY3–36 on Food Intake and Body Weight in Diet‐Induced Obese Rats

Significant weight loss following Roux‐en‐Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon‐like peptide‐1 (GLP‐1) and peptide YY_3–36 (PYY_3–36). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP‐1 homologue exendin‐4 alone and with PYY_3–36 that produces a sustained reduction in daily food intake and body weight in diet‐induced obese (DIO) rats. We tested 12 exendin‐4 strategies over 10 weeks. Exendin‐4 infused during the first and last 3 h of the dark period at 15–20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin‐4 and PYY_3–36 produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin‐4 alone and with PYY_3–36 on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin‐4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co‐infusion of exendin‐4 and PYY_3–36 does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin‐4 alone and with PYY_3–36 on food intake and body weight.