Whey Protein Hydrolysate Increases Translocation of GLUT-4 to the Plasma Membrane Independent of Insulin in Wistar Rats

Whey protein (WP) and whey protein hydrolysate (WPH) have the recognized capacity to increase glycogen stores. The objective of this study was to verify if consuming WP and WPH could also increase the concentration of the glucose transporters GLUT-1 and GLUT-4 in the plasma membrane (PM) of the muscle cells of sedentary and exercised animals. Forty-eight Wistar rats were divided into 6 groups (n = 8 per group), were treated and fed with experimental diets for 9 days as follows: a) control casein (CAS); b) WP; c) WPH; d) CAS exercised; e) WP exercised; and f) WPH exercised. After the experimental period, the animals were sacrificed, muscle GLUT-1 and GLUT-4, p85, Akt and phosphorylated Akt were analyzed by western blotting, and the glycogen, blood amino acids, insulin levels and biochemical health indicators were analyzed using standard methods. Consumption of WPH significantly increased the concentrations of GLUT-4 in the PM and glycogen, whereas the GLUT-1 and insulin levels and the health indicators showed no alterations. The physical exercise associated with consumption of WPH had favorable effects on glucose transport into muscle. These results should encourage new studies dealing with the potential of both WP and WPH for the treatment or prevention of type II diabetes, a disease in which there is reduced translocation of GLUT-4 to the plasma membrane.     

Moderate intake of BCAA-rich protein improves glucose homeostasis in high-fat-fed mice

Notwithstanding the fact that dietary branched-chain amino acids (BCAAs) have been considered to be a cause of insulin resistance (IR), evidence indicates that BCAA-rich whey proteins (WPs) do not lead to IR in animals consuming high-fat (HF) diets and may instead improve glucose homeostasis. To address the role of BCAA-rich WP as dietary protein in IR and inflammatory response, we fed C57BL/6J mice either high-fat (HF) or low-fat (LF) diets formulated with moderate protein levels (13% w/w) of either WP or hydrolyzed WP (WPH) and compared them with casein (CAS) as a reference. The muscle and plasma free amino acid profiles, inflammatory parameters and glycemic homeostasis were examined. While the LF/CAS diet promoted the rise in triglycerides and inflammatory parameters, the HF/CAS induced typical IR responses and impaired biochemical parameters. No differences in plasma BCAAs were detected, but the HF/WPH diet led to a twofold increase in gastrocnemius muscle free amino acids, including BCAAs. In general, ingestion of WPH was effective at averting or attenuating the damage caused by both the LF and HF diets. No high concentrations of BCAAs in the plasma or signs of IR were found in those mice fed an HF diet along with the hydrolyzed whey proteins. It is concluded that consumption of BCAA-rich whey proteins, especially WPH, does not result in the development of IR.     

Short term effects on bone quality associated with consumption of soy protein isolate and other dietary protein sources in rapidly growing female rats

Beneficial effects of soy protein consumption on bone quality have been reported. The effects of other dietary protein sources such as whey protein hydrolysate (WPH) and rice protein isolate (RPI) on bone growth have been less well examined. The current study compared effects of feeding soy protein isolate (SPI), WPH and RPI for 14 d on tibial bone mineral density (BMD) and bone mineral content (BMC) in intact and ovariectomized (OVX) rapidly growing female rats relative to animals fed casein (CAS). The effects of estrogenic status on responses to SPI were also explored. Tibial peripheral quantitative computerized tomography (pQCT) showed all three protein sources had positive effects on either BMD or BMC relative to CAS (P < 0.05), but SPI had greater effects in both intact and OVX female rats. SPI and E2 had positive effects on BMD and BMC in OVX rats (P < 0.05). However, trabecular BMD was lower in a SPI + E2 group compared to a CAS + E2 group. In OVX rats, SPI increased serum bone formation markers, and serum from SPI-fed rats stimulated osteoblastogenesis in ex vivo. SPI also suppressed the bone resorption marker RatLaps (P < 0.05). Both SPI and E2 increased alkaline phosphatase gene expression in bone, but only SPI decreased receptor activator of nuclear factor-kappaB ligand (RANKL) and estrogen receptor gene expression (P < 0.05). These data suggest beneficial bone effects of a soy diet in rapidly growing animals and the potential for early soy consumption to increase peak bone mass.     

Exercise-induced elevation of HSP70 is intensity dependent.

Exercise induces expression of the protective heat shock protein, HSP70, in striated muscle. To characterize the relationship between induction of this protein and exercise intensity in muscles exhibiting different recruitment patterns, male Sprague-Dawley rats were assigned to a sedentary control or one of seven exercise groups for which treadmill running speed varied between 15 and 33 m/min (n = 8/group). Twenty-four hours after a single 60-min exercise bout, hearts, red and white portions of the vastus (RV and WV, respectively) muscles, and soleus (Sol) muscles were harvested and analyzed for both relative and absolute HSP70 content. Cardiac HSP70 was significantly elevated only when animals were exercised at 24 m/min and beyond. Similarly, HSP70 was elevated in RV at running speeds above 24 m/min but did not increase in WV until 27 m/min. In contrast, HSP70 content was initially elevated in the Sol but subsequently declined at the highest running speeds. The observed patterns of HSP70 expression in skeletal muscle were in general accordance with known muscle recruitment patterns and suggest that alterations in muscle loading, resulting from changes in exercise intensity, are an important component of exercise-induced increases in HSP70 content.     

Exercise,antioxidants, and HSP72: protection against myocardial ischemia/reperfusion

Endurance exercise is associated with protection against myocardial ischemia/reperfusion (I/R) injury and has been shown to increase heat shock protein 72 (HSP72). Dietary antioxidants have also been reported to decrease I/R-induced injury. Because exercise and antioxidants may provide cardioprotection via different mechanisms, combining these countermeasures could provide additive protection. Alternatively, because exercise-induced oxidant production may promote expression of HSP72, antioxidants could attenuate exercise-induced HSP72 expression and decrease exercise-related cardioprotection. These experiments examined the individual and combined effects of exercise and antioxidants on myocardial I/R injury (in vivo). Rats receiving a mixed antioxidant diet or control diet were assigned to exercise or sedentary groups and randomized to receive: (i) short I/R (myocardial stunning), (ii) long I/R (myocardial infarction), or (iii) sham surgery. Antioxidants significantly increased total antioxidant capacity and attenuated exercise-related HSP72 accumulation. Nonetheless, during short I/R, exercise-trained animals demonstrated improved left ventricular developed pressure (LVDP), independent of diet. Further, antioxidants alone resulted in improved LVDP. Finally, compared to control diet/sedentary animals, both exercise groups (control and antioxidant diets) and the antioxidant diet/sedentary group sustained smaller infarctions. We conclude that exercise and antioxidants can independently provide protection against myocardial contractile dysfunction and infarction, and the combination of these two strategies does not enhance or inhibit the protection observed with each individual countermeasure.     

Optimization and effect of dairy industrial waste as media components in the production of hyaluronic acid by Streptococcus thermophilus

Hyaluronic acid (HA) production using a dairy industrial waste is a more cost-efficient strategy than using an expensive synthetic medium. In this study, we investigated the production of HA using Streptococcus thermophilus under shake flask conditions using dairy industrial waste as nutritional supplements, namely whey permeate (WP) and whey protein hydrolysate (WPH). Preliminary screening using Plackett–Burman design exhibited WP, WPH, initial pH, and inoculum size as significant factors influencing HA titer. Response surface methodology design of four factors was formulated at three levels for enhanced production of HA. Shake flask HA fermentation by S. thermophilus was performed under global optimized process conditions and the optimal HA titer (342.93?mg?L^?1) corroborates with Box–Behnken design prediction. The molecular weight of HA was elucidated as 9.22–9.46?kDa. The ultralow-molecular weight HA reported in this study has a potential role in drug and gene delivery applications.     

Human insulinotropic response to oral ingestion of native and hydrolysed whey protein

The insulinotropic response to the ingestion of whey protein and whey protein hydrolysate, independent of carbohydrate, is not known. This study examined the effect of protein hydrolysis on the insulinotropic response to the ingestion of whey protein. Sixteen healthy males ingested a 500 mL solution containing either 45 g of whey protein (WPI) or whey protein hydrolysate (WPH). The estimated rate of gastric empting was not altered by hydrolysis of the protein [18 (3) vs. 23 (3) min, n = 16; P = 0.15]. Maximum plasma insulin concentration (C _max) occurred later (40 vs. 60 min) and was 28% [234 (26) vs. 299 (31) mM, P = 0.018] greater following ingestion of the WPH compared to the WPI leading to a 43% increase [7.6 (0.9) vs. 10.8 (2.6) nM, P = 0.21] in the AUC of insulin for the WPH. Of the amino acids with known insulinotropic properties only Phe demonstrated a significantly greater maximal concentration [C _max; 65 (2) vs. 72 (3) μM, n = 16; P = 0.01] and increase (+22%) in AUC following ingestion of the WPH. In conclusion, ingestion of whey protein is an effective insulin secretagogue. Hydrolysis of whey protein prior to ingestion augments the maximal insulin concentration by a mechanism that is unrelated to gastric emptying of the peptide solution.     

Endurance training prevents inflammation and apoptosis in hypothalamic neurons of obese mice

This study investigated the effects of exercise training in regulating inflammatory processes, endoplasmic reticulum stress, and apoptosis in hypothalamic neurons of obese mice. Swiss mice were distributed into three groups: Lean mice (Lean), sedentary animals fed a standard diet; obese mice (Obese), sedentary animals fed a high-fat diet (HFD); trained obese mice (T. Obese), animals fed with HFD and concurrently subjected to an endurance training protocol for 8 weeks. In the endurance training protocol, mice ran on a treadmill at 60% of peak workload for 1 hr, 5 days/week for 8 weeks. Twenty-four hours after the last exercise session, the euthanasia was performed. Western blot, quantitative real-time polymerase chain reaction, and terminal deoxynucleotide transferase biotin-dUTP nick end-labeling (TUNEL) techniques were used for the analysis of interest. The results show exercise training increased phosphorylation of leptin signaling pathway proteins (pJAK2/pSTAT3) and reduced the content of tumor necrosis factor α, toll-like receptor 4, suppressor of cytokine signaling 3, protein–tyrosine phosphatase 1B as well as the phosphorylation of IkB kinase in the hypothalamus of T. Obese animals. A reduction of macrophage activation and phosphorylation of eukaryotic initiation factor 2α, and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were also observed in exercised animals. Furthermore, exercise decreased the expression of the proapoptotic protein (PARP1) and increased anti-inflammatory (IL-10) and antiapoptotic (Bcl2) proteins. Using the TUNEL technique, we observed that the exercised animals had lower DNA fragmentation. Finally, physical exercise preserved pro-opiomelanocortin messenger RNA content. In conclusion, exercise training was able to reorganize the control of the energy balance through anti-inflammatory and antiapoptotic responses in hypothalamic tissue of obese mice.     

Placental and vascular adaptations to exercise training before and during pregnancy in the rat

Although exercise during pregnancy is generally recommended and thought to be beneficial to mother and fetus, the nature of the adaptations to exercise during pregnancy and how they may be beneficial remain poorly understood. Recent studies suggest that exercise may stimulate expression of several cytoprotective and pro-angiogenic molecules such as heat shock proteins (HSP) and vascular endothelial growth factors (VEGF). We hypothesized that exercise training during pregnancy improves angiogenic balance, increases HSP expression, and improves endothelial function. Female rats were given access to an exercise wheel for 6 wk before and during pregnancy. On day 19 of pregnancy tissues were collected and snap frozen for later analysis. Western blots were performed in skeletal muscle and placenta. HSP 27 (3.7 ± 0.36 vs. 2.2 ± 0.38; P < 0.05), HSP 60 (2.2 ± 0.73 vs. 0.49 ± 0.08; P < 0.05), and HSP 90 (0.33 ± 0.09 vs. 0.11 ± 0.02; P < 0.05) were increased in the placentas of exercise-trained rats compared with sedentary controls. In addition, exercise training increased (P < 0.05) plasma free VEGF and augmented (P < 0.05) endothelium-dependent vascular relaxation compared with nonexercise control rats. The present data indicates chronic exercise training stimulates HSP expression in the placenta and that regular exercise training increases circulating VEGF in pregnant but not in nonpregnant rats. Although the present findings suggest that exercise before and during pregnancy may promote the expression of molecules that could attenuate placental and vascular dysfunction in complicated pregnancies, further studies are needed to determine the safety and effectiveness of exercise training as a therapeutic modality in pregnancy.     

Dietary whey protein modulates liver glycogen level and glycoregulatory enzyme activities in exercise-trained rats

This study compared the effects of dietary whey protein with dietary casein or soy protein on glycogen storage and glycoregulatory enzyme activities in the liver of sedentary and exercise-trained rats. Male Sprague-Dawley rats (ca. 130 g) were divided into one sedentary and three exercise-trained groups, with eight animals in each group. Casein was provided as the source of dietary protein in the sedentary group while the exercise-trained groups were fed casein, whey, or soy protein. Rats in the exercise-trained groups ran for 30 mins/day, 4 days/week on a motor-driven treadmill. In the exercise-trained rats, animals fed whey protein had higher liver glycogen content than animals in the other two diet groups. Glucokinase activity was significantly higher in rats fed whey protein compared to that in rats fed soy protein, while glucose 6-phosphatase activity was significantly decreased in animals on the whey protein diet compared with those the other two diets. Although 6-phospho-fructokinase activity was significantly lower in the whey protein group than in the soy protein group, we found that fructose 1,6-bisphosphatase activity was significantly higher in the whey group compared with either the casein or soy groups. Pyruvate kinase activity in rats fed the casein diet was significantly higher than in rats fed either the whey or soy protein diets. In addition, hepatic alanine aminotransferase activity and serum alanine level were also increased in the whey protein group compared with the casein or soy protein groups. Taken together, these results demonstrate that the whey protein diet in exercise-trained rats results in significantly higher levels of liver glycogen, because of the combined effects of regulation of rate limiting glycolytic and gluconeogenic enzyme activities and activation of glycogenesis from alanine via alanine amino-transferase.     

Food-deprivation induces HSP70 and HSP90 protein expression in larval gilthead sea bream and rainbow trout

Heat shock proteins (HSPs) expression is commonly used as indicators of cellular stress in animals. However, very little is known about either the expression patterns of HSPs or their role in the stress-tolerance phenomenon in early life stages of fish. To this end, we examined the impact of food-deprivation (12 h), reduced oxygen levels (3.5 mg/L for 1 h) and heat shock (HS: + 5 °C for 1 h) on HSP70 and HSP90 protein expression in early life stages of the gilthead sea bream (Sparus aurata), a warm-water aquaculture species. Also, we investigated HSP70 and HSP90 response to food-deprivation (7 days) in early life stages of rainbow trout (Oncorhynchus mykiss), a cool-water aquaculture species, and the tolerance of this larvae to heat shock (either + 5 or + 10 °C for 1 h). Our results clearly demonstrate that food-deprivation enhances HSP70 and HSP90 protein expression in larvae of both species. In gilthead sea bream larvae, the stressors-induced HSP70 and HSP90 (only in the reduced oxygen group) protein expression returned to unstressed levels after 24 h recovery. In fed trout larvae, a + 5 °C heat shock did not elevate HSP70 and HSP90 expression, whereas 100% mortality was evident with a + 10 °C HS. However, food-deprived trout larvae, which had higher HSP70 and HSP90 protein content, survived HS and showed HS-dependent increases in HSP70, but not HSP90 expression. Overall, HSP70 and HSP90 protein expression in early life stages of fish have the potential to be used as markers of nutritional stress, while elevation of the tissue HSPs content may be used as a means to increase stress tolerance during larval rearing.     

Effects of dietary zinc on free radical generation, lipid peroxidation, and superoxide dismutase in trained mice.

The purpose of this study was to investigate the effects of dietary zinc on free radical generation, lipid peroxidation, and superoxide dismutase (SOD) in exercised mice. In the first part of the study, 48 male weanling mice were randomly divided into three groups. They were fed a zinc-deficient diet containing 1.6 mg/kg zinc or were pair-fed or fed ad libitum a zinc-adequate diet supplemented with 50 mg/kg zinc. Half of each group received an exercise training program that consisted of swimming for 60 min per day in deionized water. The diets and exercise program persisted for 6 weeks. In the second part of the study, 64 mice were fed zinc-deficient diets for 6 weeks, and then one group was fed the zinc-deficient diet for an additional 3 weeks, and the other three groups were fed diets supplemented with 5, 50, and 500 mg/kg zinc, respectively. Half of each group also received the exercise program. Both blood and liver samples were examined. Free radicals in liver were directly detected by electron spin resonance techniques and the extent of lipid peroxidation was indicated by malonic dialdehyde (MDA). Both CuZn-SOD and Mn-SOD were measured. The results showed that exercise training increased the metabolism of zinc, and zinc deficiency induced an increased free radical generation and lipid peroxidation and a decreased hepatic CuZn-SOD activity in exercised mice. Furthermore, although exercise training had no effect on the level of free radicals in zinc-adequate mice, it could increase the hepatic mitochondrial MDA formation further in zinc-deficient animals and zinc deficiency would eliminate the exercise-induced increase in SOD activities which existed in zinc-adequate mice. A total of 50 mg/kg zinc supplemented in the diet was adequate to correct the zinc-deficient status in exercised mice while 5 mg/kg zinc had a satisfactory effect on the recovery of only sedentary zinc-deficient mice. However, 500 mg/kg zinc had a harmful effect on both sedentary and exercised zinc-deficient animals.     

结直肠癌中HSP60和HSP27表达的免疫组织化学研究

目的1观察热休克蛋白60和热休克蛋白27在结直肠癌中的表达及意义。方法：收集结直肠癌80例,其中淋巴结转移40例（转移组）,无淋巴结转移40例（无转移组）;另外,在结直肠癌80例中,有结直肠腺瘤（腺瘤组）以及距肿块15cm以上的正常肠粘膜（对照组）各40例。应用免疫组织化学SP法检测组织中蛋白的表达。结果：HSP60的表达主要定位在癌细胞胞浆,在对照组、腺瘤组、非转移组、转移组中的表达阳性率分别为25％、30％、57．5％、90％,组间比较发现,对照组与转移组、腺瘤组与转移组、转移组与非转移组（x^2=10．912,P〈0．001）的HSP60阳性表达率存在统计学差异;而对照组与腺瘤和非转移组间以及腺瘤与非转移组间无统计学差异。HSP27的表达主要定位在癌细胞的胞浆,在对照组、腺瘤组、非转移组、转移组的表达阳性率分别为5％,35％,50％,90％,组间比较发现,对照组分别与无淋巴结转移组、淋巴结转移组;腺瘤组分别与转移组;非转移组与转移组间存在统计学差异,腺瘤与非转移组间无统计学差异。HSP60和HSP27表达间无统计学相关。结论：HSP27表达可能与结直肠癌发生和转移相关。而HSP60的表达可能在结直肠癌转移中具有重要意义。     

The digestion rate of protein is an independent regulating factor of postprandial protein retention

To evaluate the importance of protein digestion rate on protein deposition, we characterized leucine kinetics after ingestion of "protein" meals of identical amino acid composition and nitrogen contents but of different digestion rates. Four groups of five or six young men received an L-[1-13C]leucine infusion and one of the following 30-g protein meals: a single meal of slowly digested casein (CAS), a single meal of free amino acid mimicking casein composition (AA), a single meal of rapidly digested whey proteins (WP), or repeated meals of whey proteins (RPT-WP) mimicking slow digestion rate. Comparisons were made between "fast" (AA, WP) and "slow" (CAS, RPT-WP) meals of identical amino acid composition (AA vs. CAS, and WP vs. RPT-WP). The fast meals induced a strong, rapid, and transient increase of aminoacidemia, leucine flux, and oxidation. After slow meals, these parameters increased moderately but durably. Postprandial leucine balance over 7 h was higher after the slow than after the fast meals (CAS: 38 +/- 13 vs. AA: -12 +/- 11, P < 0.01; RPT-WP: 87 +/- 25 vs. WP: 6 +/- 19 micromol/kg, P < 0.05). Protein digestion rate is an independent factor modulating postprandial protein deposition.     

Expression of exercise-induced HSP70 in long-distance runner''s leukocytes

This study was designed to investigate the expression of heat shock protein 70 (HSP70), after acute moderate intensity exercise, in human peripheral blood leukocytes of trained runners and untrained controls. Ten male long-distance trained runners (TR) and untrained sedentary control subjects (SED) ran for 1 h at 70% of heart rate reserve (HRR). Basal HSP70 expression in TR was usually lower than that in SED, but basal HSP70 gene expression in TR was usually higher than that in SED. Although expression rates of exercise-induced HSP70 in both groups were similar, levels of HSP70 in SED were significantly higher than in TR. Significant increases in leukocytes, neutrophils, and lymphocytes after exercise were observed in both groups, but there were some differences between groups. We conclude that 1 h treadmill running at 70% HRR intensity is a sufficient stimulus to leukocytosis, neutrocytosis, lymphocytosis, and HSP70 proteins and gene expression in leukocytes. Adaptation to training was observed in TR.     

Effects of dietary hydrolysate supplementation on growth,body composition,hematological responses,and liver histology of juvenile giant trevally (Caranx ignobilis Forsskal, 1775)

A feeding study was conducted to investigate how fish protein hydrolysate (FPH) supplementation affected the growth, feed utilization, body composition, and hematology of juvenile giant trevally (Caranx ignobilis Forsskal, 1775). Seven isonitrogenous (52% protein) and isocaloric diets (10% lipid) were formulated, wherein shrimp hydrolysate (SH) and tuna hydrolysate (TH) were used to replace fishmeal at inclusion levels of 0 (control), 30, 60, and 90 g/kg and labeled as control, SH30, SH60, SH90, TH30, TH60, and TH90, respectively. Each diet was fed to triplicate groups of juvenile giant trevally for 8 weeks. The results showed higher final body weight and specific growth rate in fish fed SH30, SH60, TH30, and TH60 than fed control diet. No difference was observed in feed intake, but reduced feed conversion ratio (FCR) was found in fish fed SH30, SH60, TH30, and TH60, demonstrating these diets improved feed utilization. TH90 caused deposition of lipid droplet in the hepatocyte, a sign of liver damage. Total monounsaturated fatty acids, polyunsaturated fatty acids (PUFA), and highly unsaturated fatty acids in fish were not affected by FPH supplementation. Fish fed TH30 showed lower ∑n − 3 PUFA than the fish fed remaining dietary treatments. The elevated serum protein was seen in fish fed control, SH30, SH60, and TH30, demonstrating that these diets were beneficial for the innate immune response in giant trevally. The results indicate that TH and SH could be incorporated into diets of giant trevally at 30–60 g/kg, replacing 7%–13% fishmeal with enhanced growth and health benefits.     

Paternal high-fat diet and exercise regulate sperm miRNA and histone methylation to modify placental inflammation,nutrient transporter mRNA expression and fetal weight in a sex-dependent manner

We previously have shown that male offspring (F1) of fathers (F0) fed a high-fat (HF) diet and that exercised had greater skeletal muscle insulin signaling and reduced type 2 diabetes mellitus (T2DM) risk compared to fathers fed HF diet and that remained sedentary. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by alterations in placental tissue growth via changes in sperm miRNA expression. To test these hypotheses, 3-week-old male C57BL/6 mice were fed a normal-fat diet (16% fat) or an HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months. Results showed that F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of dimethylated histone 3 lysine 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males. Placental interleukin-1β and tumor necrosis factor (TNF)-α mRNA expression was reduced by paternal exercise, while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. Treatment of primary placental cell with miRNA 193b inhibited TNF-α mRNA expression, and treatment of TNF-α decreased SLC38a2 mRNA expression. Moreover, paternal exercise increased body weight at weaning in a female offspring. These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise, while placental inflammatory gene expression is influenced by paternal exercise in offspring in a sex-specific manner.     

High-fat diet offsets the long-lasting effects of running-wheel access on food intake and body weight in OLETF rats

We have previously demonstrated that running-wheel access normalizes the food intake and body weight of Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Following 6 wk of running-wheel access beginning at 8 wk of age, the body weight of OLETF rats remains reduced, demonstrating a lasting effect on their phenotype. In contrast, access to a high-fat diet exacerbates the hyperphagia and obesity of OLETF rats. To determine whether diet modulates the long-term effects of exercise, we examined the effects of high-fat diet on food intake and body weight in OLETF rats that had prior access to running wheels for 4 wk. We found that 4 wk of running exercise significantly decreased food intake and body weight of OLETF rats. Consistent with prior results, 4 wk of exercise also produced long-lasting effects on food intake and body weight in OLETF rats fed a regular chow. When running wheels were relocked, OLETF rats stabilized at lower levels of body weight than sedentary OLETF rats. However, access to a high-fat diet offset these effects. When OLETF rats were switched to a high-fat diet following wheel relocking, they significantly increased food intake and body weight, so that they reached levels similar to those of sedentary OLETF rats fed a high-fat diet. Gene expression determination of hypothalamic neuropeptides revealed changes that appeared to be appropriate responses to the effects of diet and running exercise. Together, these results demonstrate that high-fat diet modulates the long-lasting effects of exercise on food intake and body weight in OLETF rats.