Long-term effects of exogenous leptin on body weight and fat in post-obese female rats.

This study was designed to test the hypothesis that short-term leptin infusion during the post-obese refeeding phase of weight-reduced rats would reduce the rate of weight regain and, as a result, reduce the final body weight and fat content in weight-reduced rats. Ninety-six female Wistar rats were divided into four groups: (1) LFCON (low-fat control) group: Rats in this group were fed the control low-fat (LF) diet ad lib for the entire study period. (2) HFCON (high-fat control) group: Rats in this group were fed the high-fat (HF, 40% fat) diet ad lib for the study period. (3) HFRLP (high-fat fed, weight-reduced, leptin treatment) group: Obese rats in this group were weight-reduced and received leptin infusion for 2 weeks (miniosmotic pumps, 0.5 microg/kg/day) during the post-obese refeeding period. (4) HFRSM (high-fat fed, weight-reduced, sham control) group: Rats in this sham-control group were treated the same as the rats in the HFRLP group with the exception that no leptin was actually infused during the first 2 weeks of refeeding period. The results demonstrated that 2 weeks of leptin treatment during the early refeeding phase did not prevent weight regain in weight-reduced rats, but it significantly reduced body fat content in these rats as compared to ad lib fed obese control rats. One cycle of weight reduction and regain did not alter the body weight and body fat content in HFRSM rats when compared to obese control rats. Therefore, leptin treatment was effective in reducing body fat content in post-obese rats for up to 7 weeks, but the long-term effect of short-term leptin treatment needs to be further examined.     

Effects of alternations (10 days) of high-fat with normal diet on liver lipid infiltration, fat gain, and plasma metabolic profile in rats

The purpose of the present study was to test the hypothesis that short-term alternations of high-fat with normal chow feeding result in higher fat accumulation in liver than continuous intake of the same high-fat diet. Male Sprague-Dawley rats (7 weeks of age) were divided into 3 groups according to diet composition: standard chow (SD; 12,5% kcal as fat), high-fat (HF; 42% kcal as fat), and food cycles (FC) consisting of 10-day alternations between HF and SD diets beginning with the high-fat diet. Rats in each of these 3 groups were sacrificed after 10, 30, and 50 days (n = 10 rats/sub-groups). Energy intake, body weight, liver and muscle relative weights were not significantly (P > 0.05) different between FC- and HF-fed rats. Using the total energy intake for the 50-day period, it was calculated that approximately 30% less calories as fat was ingested in the FC- compared to the HF-fed rats. In spite of this, liver lipid infiltration as well as fat accretion in abdominal adipose tissues were increased (P < 0.01) similarly in FC- and HF-fed rats. Plasma FFA and insulin levels depicted strong tendencies (P < 0.07) to be higher in FC- than in continuous HF-fed rats at the end of the 50-day period. These results indicate that, despite a 30% reduction in ingested lipids, alternations of HF with normal chow diet compared to the continuous hyperlipidic diet caused the same level of infiltration of lipids in the liver and in the abdominal adipose tissues and, to a certain extent, may even result in a larger deterioration of the metabolic profile.     

Consumption of a high-fat diet alters the homeostatic regulation of energy balance

Humans in many countries are currently experiencing what has been called an epidemic of obesity. That is, the average body weight (and amount of fat stored in the body) is increasing over years, carrying with it a multitude of associated medical, psychological, and economic problems. While there is no shortage of possible causes of this epidemic, increased availability and consumption of high-fat (HF), calorically dense and generally quite palatable food is often touted as a likely culprit. In order to better assess the impact of consuming a diet with those qualities, we have developed a well-controlled animal model in which the effects of chronic consumption of a high-fat diet can be dissociated from those of becoming obese per se. Long-Evans rats are fed one of two semipurified pelleted diets, a HF diet that contains 20% fat by weight and a low-fat (LF) diet that contains 4% fat by weight. Pair-fed animals consume the HF diet but are limited to the daily caloric intake of LF rats. Another group receives pelleted chow. Relative to animals consuming diets low in fat, HF animals weigh more, have more carcass fat, are hyperinsulinemic and hyperleptinemic, and are insulin resistant. HF-fed animals, independent of whether they become obese or not, also have central insulin and MTII insensitivity. Finally, HF rats have a down-regulated hypothalamic apo A-IV system that could contribute to their hyperphagia.     

High fat/sucrose feeding attenuates the hypertension of spontaneously hypertensive rats

To assess the caloric and cardiovascular effects of dietary obesity on an important animal model of hypertension research, 60-day-old male spontaneously hypertensive (SHR) rats were fed either Agway pelleted chow (Pellet), a diet enriched in fat and sucrose (HF/M), or alternated (Cycled) between 2-week periods of HF/M diet and Agway pelleted chow. After 14 weeks, HF/M feeding elevated the body weight of SHR rats by 15% over the body weight of pellet-fed control rats. This relative obesity was accompanied by heavier white (retroperitoneal) and brown (interscapular) fat pads, heavier heart weights, and tachycardia. Paradoxically, the systolic blood pressure levels of SHR rats fed the HF/M diet were reduced. Ruled out as an explanation for the blood pressure reduction was the relative polyunsaturated to saturated fat (P/S) rati of the diet. The hypertension of SHR rats may be due in part to the effects of an underlying metabolic problem that is counteracted by the effects of HF/M feeding; HF/M feeding not only elevated body weight but also reversed the hypoinsulinemia found in pellet-fed SHR rats. The Cycled group evidenced large up-and-down swings in caloric intake that coincided with HF/M and Pellet feeding; this produced modest staircase-like changes in body weight gain. Similar to the HF/M group, the systolic blood pressure level of the Cycled group was also reduced in comparison to the blood pressure level of the Pellet group. However, the Cycled group was found to be more responsive to the pressor effects of intravenous phenylephrine, an alpha-adrenergic agonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin

Obesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptin-resistance is present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amylin sensitivity is inversely correlated with adiposity, such that DIO reduces the anorectic action of acute amylin. We also determined if hyperamylinemia leads to a change in amylin sensitivity. In the first experiment, rats were chronically exposed to a high fat (HF; 60% fat) diet or fed standard chow for control. The anorectic response to amylin was tested on several occasions over a 14 week observation period. HF feeding led to the expected increase in body adiposity; the response to an acute amylin injection (5 - 50 μg/kg s.c.) was unaltered for 10 weeks of HF feeding. Even after 12 weeks on a HF diet, which clearly caused obesity, acute administration of amylin (5 μg/kg, s.c.) was still able to suppress food intake, although the suppression was not statistically significant. Further experiments using additional doses of amylin will be necessary to demonstrate possible amylin resistance after HF feeding or in DIO rats. In the second experiment, we tested more specifically whether hyperamylinemia that may result from HF feeding and subsequent obesity, reduces the sensitivity of the amylin signaling system. To avoid confounding factors, we chronically infused lean chow fed rats with amylin (5 or 10 μg/kg/day s.c.) to elevate their plasma amylin concentration to levels observed in obese rats (30 - 40 pM). In the absence of obesity, hyperamylinemia did not lead to a reduced sensitivity to acute amylin (5 - 20 μg/kg s.c.) injections; acute amylin reduced eating similarly in all groups of rats. Overall, we concluded that direct diet effects by short term exposure to HF appear to be of little importance for amylin sensitivity; further, long-term maintenance on a HF diet and the resulting obesity only slightly attenuated the anorectic response to acute amylin. Because we observed no marked changes in amylin sensitivity in lean, chow fed rats with induced hyperamylinemia, amylin receptor downregulation in chronic hyperamylinemia does not seem to occur.     

不同时间进食高脂或高蛋白食物与肥胖的关系

目的：探讨不同时间段进食高脂肪或者高蛋白饲料对小鼠肥胖程度的影响。方法：将108只3～4周龄健康清洁级雄性昆明小白鼠随机分为3大组：高脂组、高蛋白组和对照组。喂食时间段为：T1（17∶00～19∶00）,T2（22∶00～24∶00）和T3（7∶00～9∶00）。高脂组又分为4小组：HF0,HF1、HF2、HF3。HF0在三时段均喂食高脂饲料,HF1、HF2、HF3分别于时段T1,T2和T3喂食高脂饲料,其余时段喂食普通饲料。高蛋白组分为HP0,HP1、HP2、HP3,分组原理同高脂组。对照组在三个时段均喂食普通饲料。三组小鼠其它时间不予进食,饮水不限,连续喂养8w后,称重,并计算小鼠的体重增加值及测量内脏脂肪系数。结果：高脂组增重：与对照组相比,实验组增重明显,但组间差异没有统计学意义。高蛋白组增重：17∶00～19∶00高蛋白组（HP1）及7∶00～9∶00高蛋白组（HP3）相比对照组有显著增重,三餐高蛋白组（HP0）、22∶00～24∶00高蛋白组（HP2）组、对照组三组之间差别没有统计学意义。无论是高脂组还是高蛋白组的内脏脂肪系数与对照组比较,结果没有统计学意义（P〉0.05）。结论：无论哪一餐进食高脂饲料,或者三餐都进食高脂饲料,相较于对照组都会使小鼠增重明显。而三餐高蛋白组（HP0）相较于对照组没有显著增重;22∶00～24∶00高蛋白组（HP2）相较于对照组没有显著增重;22∶00～24∶00高蛋白组（HP2）相较于三餐高蛋白组（HP0）也没有显著增重。该结论对研究人类肥胖问题有现实参考意义。     

Diet composition alters the satiety effect of cholecystokinin in lean and obese Zucker rats

Although exogenous administration of the peptide cholecystokinin (CCK) has been shown to reduce food intake in a variety of experimental situations, few studies have examined the influence of dietary content upon CCK's effectiveness, particularly in obese states. To evaluate the effectiveness of CCK administration in animals consuming high fat diets, groups of obese and lean Zucker rats were maintained on laboratory chow (CH), a high fat diet isocaloric to chow (IF), or a hypercaloric fat diet (HF). After a 17 hr fast, rats were given intraperitoneal injections of saline or ascending doses of 0.06 to 2.0 micrograms/kg of the synthetic octapeptide of CCK. On all diets, obese rats required higher doses of CCK to significantly reduce feeding and showed smaller intake reductions than lean rats (p less than 0.001). Despite higher baseline caloric intakes (p less than 0.001), rats of both genotypes maintained on HF displayed larger reductions of intake than those fed IF or CH (p less than 0.001). Intake reductions by either genotype maintained on IF or CH were not reliably different. The manner in which the satiety effect of CCK was enhanced in rats consuming the calorically dense, palatable HF diet is unclear but may be related to orosensory and/or postingestive attributes of the diet.     

Self-selecting albino rats exhibit differential preferences for pure macronutrient diets: Characterization of three subpopulations

Analyses of natural feeding behavior in albino male Sprague-Dawley rats demonstrate that, when allowed to self-select from pure macronutrient diets (protein, carbohydrate and fat), these rats of the same genetic strain can be categorized into 3 subpopulations according to either their 24-h or their 12-h nocturnal patterns of nutrient intake. A majority of the animals (HC for high carbohydrate, 50% of the total population) consumed a diet rich in carbohydrate relative to protein or fat, while a smaller population of rats (HF, 30%) preferred the fat diet, and an even smaller population (HP, 20%) chose a high-protein diet. These 3 subpopulations, after a few weeks of maintenance on the diets, differed in their body weight, with the HF rats having a higher body weight than the HP animals, who tended to weigh more than the lightest HC rats. Whereas all subgroups exhibited a similar bimodal distribution of feeding during the nocturnal cycle, with peaks during the early and late dark periods, they were distinguishable on the basis of their nutrient consumption during specific phases of the dark cycle. This difference was most apparent in the early dark phase, when the 3 subgroups exhibited exaggerated preferences for the specific nutrient that was generally preferred over the 24-h cycle. This is in contrast to the middle dark phase, when diet preferences were attenuated or lost, and the late dark phase, when most rats were similar in showing an increased preference for protein and fat and a decreased preference for carbohydrate. The HF group was further distinguished by an unusually strong burst of feeding during the first 2 h of the dark period and an extra peak of feeding in the middle dark period (7th h), both of which were relatively high in fat content.     

Relationship of dietary fat content to food preferences in young rats

Weanling rats were fed either a high-fat (30% of calories) or a low-fat (10% of calories) diet for four weeks, after which fat preference was assessed using a choice paradigm. Fat preference was measured during 2-hour intake tests in which three peanut butter/peanut oil mixtures containing 0.50, 0.61, and 0.71 grams fat/gram were offered to each animal. Rats fed the high-fat (HF) diet preferred the highest-fat mixture and consumed more total fat during intake tests than animals fed the low-fat (LF) diet. Intake of NaCl and sucrose solutions was measured during separate intake tests. LF-fed rats drank more NaCl solution than HF-fed rats. Following these tests a subgroup of the LF-fed animals was fed the HF diet, and a subgroup of the HF-fed group was fed the LF diet for a further four weeks. Upon repetition of the intake tests, rats that had been fed the HF diet during the initial four weeks still preferred the highest-fat mixture.     

Chronic food restriction and reduced dietary fat: risk factors for bouts of overeating

The purpose of this study was to determine the effect of chronic food restriction and reduced dietary fat on feeding behavior and body weight. Young female rats were fed ad lib or food restricted on a low-fat (LF) or a fat-free (FF) diet for 4 weeks. Rats then received 24-h free access to 2 diets, the maintenance diet (LF or FF) plus a novel high-fat (HF) diet (24-h intake test). After the test, all the rats were allowed chronic free access to the HF diet until body weight was stable. During the 24-h test, the restricted groups ate significantly more calories than the ad lib groups, and the FF-restricted rats ate significantly more total food, carbohydrate and protein than the LF-restricted rats; there were no differences between the two ad lib groups. During chronic free access to the HF diet, the formerly restricted rats achieved and defended lower body weights than the formerly non-restricted rats. Throughout the experiment, the ad lib groups had more body fat than the restricted groups independent of the dietary subgroup. Hence, a history of chronic food restriction predisposes to consuming more food in acute feeding situations, particularly when dietary fat is reduced, and lowers the level of body weight maintained and defended. Chronic food restriction accompanied by reduced dietary fat may increase risk for bouts of overeating.     

Changes in satiety hormones and expression of genes involved in glucose and lipid metabolism in rats weaned onto diets high in fibre or protein reflect susceptibility to increased fat mass in adulthood

Risk of developing obesity and diabetes may be influenced by the nutritional environment early in life. We examined the effects of high fibre or protein diets on satiety hormones and genes involved in glucose and lipid metabolism during postnatal development and on adult fat mass. At 21 days of age, Wistar rat pups were weaned onto control (C), high fibre (HF) or high protein (HP) diet. Tissue and blood were collected at 7, 14, 21, 28 and 35 days after birth. A second group of rats consumed the weaning diets until 4 months when they were switched to a high fat–high sugar diet for 6 weeks, after which body and fat mass and plasma glucose were determined. In young rats, HF diet increased plasma glucagon-like peptide (GLP-1) compared to C and HP and decreased leptin compared to C at postnatal days 28 and 35. Hepatic fatty acid synthase mRNA was down-regulated by HF and HP compared to C at days 28 and 35. In brown adipose tissue, HF increased uncoupling protein-3 mRNA whereas HP increased mRNA of the inflammatory cytokine interleukin-6. Body weight, fat mass and glycaemia in adult males and fat mass in females were greater after the high fat challenge in rats that consumed the HP diet from weaning. Increasing fibre or protein in postnatal diets causes rapid change in satiety hormone secretion and genes involved in glucose and lipid metabolism which appear to influence fat mass and glycaemia in adulthood, high protein being associated with increased susceptibility to obesity.     

Adipose tissue lipoprotein lipase activity in rats maintained at a reduced body weight

Male rats fed a cellulose-diluted diet maintained a reduced body weight. Adipose tissue lipoprotein lipase (LPL) activity decreased after two days of cellulose feeding, but was not different from chow-fed control levels with weight stabilized at 90% or 70% of the control group. Plasma triglyceride concentration decreased with weight loss and remained depressed with stabilized reduced weight. Regaining lost weight had no effect on LPL activity when compared with chow-fed controls or with levels obtained for the weight-reduced group. However, plasma triglyceride concentration returned to chow-fed control levels with weight gain. The disparity between these results and those obtained in obese human beings lends support to the hypothesis that the increase in adipose tissue LPL activity in weight-reduced obese human beings is indicative of a defect in regulation of adipose tissue metabolism.     

Sex differences in the effects of high-fat feeding on behavior and carcass composition

Male and female Sprague-Dawley rats were fed a high-fat diet (40% by weight) for 11 weeks beginning at 70–80 days of age. At the end of the 11th week, high-fat fed rats of both sexes were significantly heavier than chow-fed controls. All rats were then food deprived and were trained to bar-press in an operant chamber for Noyes pellets. Testing on fixed ratio (FR) schedules started when their body weights reached 85% of pre-deprivation levels and they pressed bar steadily. At the end of operant testing, all rats were refed their previous diet until body weights returned to pre-deprivation levels. The animals were then sacrificed. Fat pads from retroperitoneal, inguinal and gonadal regions were dissected out and cellularity determined. Carcass composition was analyzed by chemical methods. On the operant apparatus, the high-fat fed female rats (F-HF) behaved more like VMH lesioned obese rats, i.e. decreased bar pressing responses when compared with controls. No difference in operant responding was found between males fed high-fat diet and chow. Fat cell number and size were increased in retroperitoneal and inguinal fat pad for rats fed high-fat diet. In gonadal pads, only cell size was increased. Females on the high-fat diet had higher percentages of body fat than males on the high-fat diet. The behavioral difference in F-HF rats could be attributed to their higher adiposity. The results support previously reported findings on the behavior and adipose tissue cellularity of dietary obese rats.     

No persistent effect of preweaning nutrition on postweaning food intake, feeding efficiency, or body energy stores in Long-Evans rats.

The purpose of this study was to determine the relative importance of pre- and postweaning nutrition on body mass, body fat, and feeding efficiency in Long-Evans rats up to a period of 18 weeks following weaning. Female rats were bred and pups were redistributed to form large (14-19 pups), normal (11-13 pups) and small (4 pups) litter groups. Weaned rats were housed as pairs (40 pairs) or singletons (n = 16) and fed either a mixed-fat diet (36.6% fat) or a standard chow diet (13.5% fat). Food intake, body mass, and feeding efficiency were measured at 4, 8, 12, and 18 weeks postweaning. Total body fat and depot fat pad mass were also measured at 18 weeks postweaning. At weaning, pups from small litters were fatter (p less than 0.001), and had a greater mass (p less than 0.03) than pups from large litters. There were no persistent effects of preweaning litter size after covarying for preweaning mass on body mass, and postweaning growth, food intake, feeding efficiency, or body fat accretion. Male rats ingesting the mixed-fat diet had a greater body mass (p less than 0.05), greater body fat accretion (p less than 0.008) and a higher feeding efficiency (p less than 0.001) than their chow-fed counterparts, despite an overall lower energy intake (p less than 0.05). Female rats ingesting the mixed-fat diet had a lower food energy intake (p less than 0.005) and a greater feeding efficiency (p less than 0.001) than chow-fed rats during the early postweaning period, only. Thus, postweaning nutrition may play a more important role in postweaning adult mass and depot fat in freely eating rats than early nutritional experiences.     

Diet composition determines course of hyperphagia in developing Zucker obese rats

Previous observations from this laboratory indicate that, during growth, the hyperphagia of the male genetically obese Zucker rat reaches a peak or "breakpoint" and then declines. To examine the effect of dietary macronutrient content on the course of hyperphagia, groups of male lean and obese rats were maintained from 5-28 weeks of age on powdered chow, or isocaloric diets (3.6 kcal/g) containing 72% of calories as corn oil, dextrose, or soy isolate protein (n = 5 lean and obese rats/diet). On chow, hyperphagia was maintained at a level of 7-8 g above lean control intake until a "breakpoint" was reached at 17 weeks, and obese intake declined to lean control level. On the fat diet, hyperphagia was increased to 10 g/day when a breakpoint was reached at 8 weeks. On the dextrose and protein diets, hyperphagia at a level of 3-4 g/day reached breakpoints at weeks 18 and 16, respectively. On all diets, the intakes of obese rats were precisely equal to the intakes of lean control rats by weeks 19-20. These data show that the magnitude and duration of hyperphagia in the developing obese rat are influenced by diet composition. Previously, we have proposed that the obese rat's hyperphagia arises from rapid adipocyte filling. Since high-fat diets facilitate adipocyte enlargement, the early "breakpoint" of hyperphagia seen with the high-fat diet may indicate that this feeding stimulation decreases as the fat cells of the obese rat approach maximal size.     

Post weaning high fat feeding affects rats' behavior and hypothalamic pituitary adrenal axis at the onset of puberty in a sexually dimorphic manner

Feeding adult rats with high fat (HF) diets can alter their hypothalamic pituitary adrenal (HPA) axis responsiveness. In the present study, we examined the effect of a high fat diet, applied in rats from weaning to puberty, on their behavior and HPA axis status at puberty onset. Wistar rats of both sexes were fed postweaning with two diets containing either 24% fat (high fat, HF) or 4.3% fat (normal chow) by weight. HF enhanced puberty onset in female rats, without increasing body weight gain in either sex, compared with chow-fed animals. In the forced swim test, HF males exhibited a more active behavioral response on the first day, whereas HF females a more passive response during the second day of the test, as compared with their chow-fed counterparts. In the open field test, HF females showed increased sniffing but reduced rearing, compared with chow-fed females and were less explorative than HF males in the central arena. All animals could learn and recall a water maze task though HF males spent more time in the opposite quadrant than chow-fed males during memory test. The HPA axis status of these animals was investigated under basal conditions. Pubertal fat-fed males had lighter adrenals, while females heavier ones, compared with their counterparts. In addition, plasma corticosterone levels of female rats were increased and glucocorticoid receptor levels in their hypothalamus were reduced due to fat diet, while in males no such changes were detected. We conclude that HF feeding during the prepubertal period can affect behavior and the HPA axis of rats at puberty onset, well before the appearance of the obese state, in a sexually dimorphic manner. Fat diet impacted more the female HPA axis, suggesting that their system is more sensitive to fat-induced nutritional imbalance during adolescence. Present data suggest that the fat-induced nutritional imbalance in young females may lead to neuroendocrine dysfunction that in turn may trigger the appearance of stress-related disorders during adolescence.     

Time course of liver lipid infiltration in ovariectomized rats: impact of a high-fat diet

OBJECTIVES: The present study was undertaken to determine the time course of liver lipid infiltration in ovariectomized (Ovx) rats and the impact of high-fat (HF; 42% kJ) feeding on this response. METHODS: In a first step, Ovx rats were compared to Sham-operated (Sham) and Ovx rats supplemented with 17beta-estradiol (OvxE2) to evaluate the effect of estrogen removal. In a second time, Ovx rats fed a HF diet (OvxHf) were compared with normally fed Ovx rats. Animals were killed after 3, 8, and 13 weeks of their respective treatment (n=8 rats/group). We measured liver triacylglycerol (TAG) content, fat pad mass, and several other plasma parameters. RESULTS: Ovariectomy resulted in the typical increase in energy intake and body weight. Liver TAG accumulation was 35, 43, and 99% higher in Ovx than in Sham rats after 3, 8, and 13 weeks, respectively. The ovariectomy-induced liver lipid infiltration was completely prevented by estrogen replacement. On the opposite, plasma TAG concentrations were lower in Ovx than in Sham and OvxE2 rats. HF feeding in Ovx rats resulted in a significant (P<0.05; 38 versus 22 mg/g at 13-week) accumulation of fat in liver as compared to normally fed Ovx rats. CONCLUSIONS: Ovariectomy results in a progressive accumulation of fat in liver over a 13-week period. In addition, HF feeding in Ovx rats lead to an even more severe liver lipid infiltration. These data indicate that the absence of estrogens in rat favours fat accretion in liver, which is highly amplified by a HF diet.     

限食对高脂喂养大鼠肝脏内质网应激的影响

目的：观察限食对高脂喂养大鼠肝脏内质网应激标志伴侣蛋白78 kD糖调节蛋白（GRP78）mRNA表达的影响，以进一步了解饮食控制对肥胖及胰岛素抵抗影响的机制。方法：雄性Wistar大鼠24只，随机分为正常对照组（NC）、高脂饮食组（HF）、热卡限制组（CR），每组8只。NC组和HF组分别给予普通饲料（脂肪热卡比18.94%）和高脂饲料（脂肪热卡比50.55%）喂养12周，自由进食。CR组给予自由高脂饲料8周后，改为半量正常饲料（半量为同龄对照组自由进食量的一半）继续喂养4周。造模结束后检测动物胰岛素抵抗指数（HOMAIR）、内脏脂肪重量/体重比值和血清生化指标变化，光镜和电镜下观察大鼠肝脏组织学改变，RT-PCR半定量检测大鼠肝脏GRP78 mRNA的表达。结果：（1）HF组空腹血胰岛素(FIns) (27.51±3.51) mU/L vs (15.46±2.25) mU/L、甘油三酯（TG）(1.35±0.25) mmol/L vs (0.67±0.10) mmol/L、胆固醇（TC）(2.59±0.34) mmol/L vs (1.41±0.28) mmol/L及胰岛素抵抗指数HOMAIR(5.85±0.23) vs (2.85±0.60)较NC组明显升高(P＜0.01)，且肝脏中脂质沉积明显。（2）限食4周后，CR组的Fins(11.25±2.42) mU/L vs (27.51±3.51) mU/L、TG(0.45±0.06) mmol/L vs (1.35±0.25) mmol/L、TC(1.06±0.15) mmol/L vs (2.59±0.34) mmol/L和HOMAIR(1.91±0.38) vs (5.85±0.23)明显低于HF组(P＜0.01)，同时肝脏中脂质沉积也减轻。（3）电镜下，HF组内质网肿胀断裂，核糖体脱落，糖原溶解，CR组则基本恢复正常。（4）HF组大鼠肝脏中GRP78 mRNA表达明显高于NC组（29.36±3.54 vs 16.51±1.73），而CR组则明显低于HF组（13.70±2.35 vs 29.36±3.54）。结论：合理限制饮食能有效减轻高脂喂养所致的脂质代谢紊乱和胰岛素抵抗，其作用机制至少与肝脏组织中的内质网应激相关蛋白GRP78的mRNA表达受抑有关。     

Energy balance and hypothalamic effects of a high-protein/low-carbohydrate diet

Diets high in fat or protein and extremely low in carbohydrate are frequently reported to result in weight loss in humans. We previously reported that rats maintained on a low-carbohydrate-high fat diet (LC-HF) consumed similar kcals/day as chow (CH)-fed rats and did not differ in body weight after 7 weeks. LC-HF rats had a 45% decrease in POMC expression in the ARC, decreased plasma insulin, and increased plasma leptin and ghrelin. In the present study we assessed the effects of a low-carbohydrate-high-protein diet (HP: 30% fat, 65% protein, and 5% CHO) on body weight, caloric intake, plasma hormone levels and hypothalamic gene expression. Male rats (n=16) were maintained on CH or HP for 4 weeks. HP rats gained significantly less weight than CH rats (73.4+/-9.4 and 125.0+/-8.2 g) and consumed significantly less kcals/day (94.8+/-1.5 and 123.6+/-1.1). Insulin was significantly reduced in HP rats (HP: 1.8+/-0.6 vs. CH: 4.12+/-0.8 ng/ml), there were no differences between groups in plasma leptin and plasma ghrelin was significantly elevated in HP rats (HP: 127.5+/-45 vs. CH: 76.9+/-8 pg/ml). Maintenance on HP resulted in significantly increased ARC POMC (HP: 121+/-10.0 vs. 100+/-5.9) and DMH NPY (HP: 297+/-82.1 vs. CH: 100+/-37.7) expression compared to CH controls. These data suggest that the macronutrient content of diets differentially influences hypothalamic gene expression in ways that can affect overall intake.     

小檗碱改善高脂饮食大鼠的胰岛素抵抗

目的:观察小檗碱是否能改善高脂饮食诱导的胰岛素抵抗,以探讨小檗碱干预糖耐量受损(IGT)的可能性。方法:8周龄雄性SD大鼠29只,分为正常组(NC,n=9)和高脂组(HF,n=20)。高脂饲料喂养14周后高脂组分为二组,10只大鼠继续喂养高脂饮食,另一小檗碱组(HF B,n=10)每天灌胃小檗碱150mg/kg体重,治疗6周后进行口服葡萄糖耐量试验和胰岛素耐量试验(ITT),评估小檗碱对胰岛素敏感性的影响。结果:HF组大鼠体重、肝重和附睾脂肪重量均明显高于HF B和NC组(均P<0.01),HF B组空腹血糖和葡萄糖负荷后2h血糖明显低于HF组(分别为5.70±0.52mmol/Lvs6.66±0.51mmol/L和7.88±0.46mmol/Lvs8.85±1.01mmol/L),空腹和葡萄糖负荷后2h胰岛素HF B组也显著低于HF组(分别为0.63±0.25ng/mlvs1.64±0.68ng/ml和1.20±0.21ng/mlvs3.60±0.36ng/ml)。各时间点血糖和胰岛素HF组均显著高于NC组(均P<0.01)。Homa胰岛素抵抗指数HF组明显高于HF B组(P<0.01)。ITT腹腔注射胰岛素后各时间点血糖下降幅度HF B组均高于HF组,15min时HF B组血糖下降23%,而HF组仅下降7%。结论:长期高脂饮食可导致大鼠胰岛素抵抗,小檗碱明显降低高脂大鼠的高胰岛素血症,改善胰岛素抵抗,因此适合于IGT的干预。