硫辛酸对高脂饮食小鼠肠道氧化还原状态及消化吸收功能的影响

目的:探讨抗氧化剂硫辛酸（LA）对高脂饮食小鼠肠道氧化还原状态调节及消化吸收功能的影响。方法:24只C57BL/6雄性小鼠,随机分为3组：即对照组(正常饮食)、高脂组(高脂饮食)、LA组(高脂饮食+0.1%LA),6周后测定活性氧(ROS)、超氧化物歧化酶（SOD）、丙二醛(MDA)和总抗氧化能力(TAC)以及脂肪酶、淀粉酶、胰蛋白酶等消化酶指标,同时用Affymetrix MOE430A 基因芯片分析肠道抗氧化、消化吸收相关功能基因的表达。结果:与高脂组相比,LA组MDA和ROS含量显著降低(P<0.05),SOD和TAC明显升高,消化酶活力有所恢复。抗氧化剂LA上调高脂饮食小鼠肠道抗氧化相关功能基因的表达水平,恢复物质消化、吸收和转运等相关功能基因的表达水平。结论:高脂引发氧化－抗氧化系统失衡,硫辛酸通过直接清除自由基以及提高抗氧化通路相关功能基因的表达水平解除氧化应激而有助于防治高脂引发的肠道功能损伤。     

CCK(1) receptor is essential for normal meal patterning in mice fed high fat diet

Cholecystokinin (CCK), released by lipid in the intestine, initiates satiety by acting at cholecystokinin type 1 receptors (CCK(1)Rs) located on vagal afferent nerve terminals located in the wall of the gastrointestinal tract. In the present study, we determined the role of the CCK(1)R in the short term effects of a high fat diet on daily food intake and meal patterns using mice in which the CCK(1)R gene is deleted. CCK(1)R(-/-) and CCK(1)R(+/+) mice were fed isocaloric high fat (HF) or low fat (LF) diets ad libitum for 18 h each day and meal size, meal frequency, intermeal interval, and meal duration were determined. Daily food intake was unaltered by diet in the CCK(1)R(-/-) compared to CCK(1)R(+/+) mice. However, meal size was larger in the CCK(1)R(-/-) mice compared to CCK(1)R(+/+) mice when fed a HF diet, with a concomitant decrease in meal frequency. Meal duration was increased in mice fed HF diet regardless of phenotype. In addition, CCK(1)R(-/-) mice fed a HF diet had a 75% decrease in the time to 1st meal compared to CCK(1)R(+/+) mice following a 6 h fast. These data suggest that lack of the CCK(1)R results in diminished satiation, causing altered meal patterns including larger, less frequent meals when fed a high fat diet. These results suggest that the CCK(1)R is involved in regulating caloric intake on a meal to meal basis, but that other factors are responsible for regulation of daily food intake.     

Decreased irisin secretion contributes to muscle insulin resistance in high-fat diet mice

Aims: Recent studies have revealed the relationship between irisin and insulin signaling, while positive associations of muscle FNDC5 with insulin resistance is observed. However, the functional mechanism of irisin on muscle insulin resistance is still obscure. This study aims to investigate the effect of irisin on muscle insulin action. Methods: Diabetic mouse model was established by high fat diet (HFD) induced obesity in C57BL/6 mice. Body indexes and serum levels of triglyceride (TG), blood glucose and insulin were record. Oral glucose tolerance test (OGTT) was performed before being killed. Circulating irisin level was also detected, while FNDC5/irisin expression was determined by RT-PCR and western blot analysis in both muscle and adipose tissues. Insulin action was further evaluated by the phosphorylation of AKT and Erk, and palmitic acid treated muscle cells were introduced for mimicking diabetic status in vitro. Results: Obvious obese feathers associated with type 2 diabetes were observed in HFD feeding mice, with decreased circulating irisin level and FNDC5/irisin secretion in adipose tissues. Although FNDC5/irisin expression showed little change in skeletal muscle, the insulin action was inhibited significantly. Moreover, palmitic acid treated muscle cells showed similar inhibition of insulin action, and FNDC5/irisin expression change. Besides, insulin action could be reversed by irisin addition in muscle cells. Conclusion: HFD induced obese mice showed decreased irisin secretion from adipose tissues, which might contribute to muscle insulin resistance. Furthermore, irisin addition could recover insulin action in palmitic acid treated muscle cells, indicating the importance of irisin for preserving insulin signaling.     

Role of gut microflora in the development of obesity and insulin resistance following high-fat diet feeding

A recent growing number of evidences shows that the increased prevalence of obesity and type 2 diabetes cannot be solely attributed to changes in the human genome, nutritional habits, or reduction of physical activity in our daily lives. Gut microflora may play an even more important role in maintaining human health. Recent data suggests that gut microbiota affects host nutritional metabolism with consequences on energy storage. Several mechanisms are proposed, linking events occurring in the colon and the regulation of energy metabolism. The present review discusses new findings that may explain how gut microbiota can be involved in the development of obesity and insulin resistance. Recently, studies have highlighted some key aspects of the mammalian host-gut microbial relationship. Gut microbiota could now be considered as a "microbial organ" localized within the host. Therefore, specific strategies aiming to regulate gut microbiota could be useful means to reduce the impact of high-fat feeding on the occurrence of metabolic diseases.     

Inflammation,diet, and type 2 diabetes: a mini-review

ABSTRACT

Inflammation is a common feature of type 2 diabetes (T2D). Inflammatory cytokines increase in patients with type 2 diabetes, metabolic syndrome, and heart disease. Various types of cells can produce inflammatory cytokines and then release them into the bloodstream, where their complex interactions with target tissues raise a tissue-specific immune response. This review focused on C-reactive protein (CRP), tumor necrosis factor (TNF)-α as an inflammatory cytokine, and adiponectin produced by adipose tissues. Despite the major role of cytokines in the development of T2D, further studies are required to investigate the possible effects of the macronutrient composition of diet on these cytokines.     

谷氨酰胺对高脂饮食诱导C57BL/6J小鼠肥胖和胰岛素抵抗的影响

目的:探讨谷氨酰胺(L-glutamine,Gln)对高脂饮食(high-fat diet,HFD)诱导小鼠肥胖和胰岛素抵抗的影响。方法:60只雄性C57BL/6J小鼠随机分为正常对照(normal control,NC)组、HFD组、HFD+丙氨酸(Lalanine,Ala)组和HFD+Gln组,每组15只。每周记录小鼠体重,给药16周后禁食不禁水12 h测定空腹血糖(fasting blood glucose,FBG),处死后剖腹取附睾脂肪垫并称重。采用酶联免疫法检测小鼠胰岛素(insulin,INS)、瘦素(leptin,LEP)、脂联素(adiponectin,APN)和胰高血糖素样肽1(glucagon-like peptide-1,GLP-1)的水平,并计算胰岛素抵抗指数(insulin resistance index,IRI)和胰岛素敏感指数(insulin sensitivity index,ISI)。结果:与NC组比较,HFD组小鼠体重和附睾脂肪垫重量明显升高,FBG、INS、IRI和LEP水平均明显升高,ISI和APN水平明显降低(P0.05);与HFD组比较,HFD+Gln组小鼠体重明显下降,FBG和LEP水平明显降低,IRI明显减小(P0.05)。4组小鼠血清的GLP-1水平差异无统计学显著性。结论:谷氨酰胺减轻高脂饮食诱导的肥胖小鼠体重和胰岛素抵抗。     

Chronic social stress in a changing dietary environment

The human population has slowly transformed from the "hunter-gatherer" period to the current environment of high energy consumption, minimal physical activity and a lifestyle that includes stress and anxiety. Modeling the current environment in the laboratory can help to elucidate mechanisms responsible for the development of obesity, diabetes and, ultimately, the metabolic syndrome. Using the visible burrow system (VBS) model of social stress we have begun to examine the short- and long-term consequences of chronic social stress on energy homeostasis. We demonstrated that social stress has significant effects on body weight and body composition such that subordinate rats progressively develop characteristics of obesity and have additionally determined that this occurs, in part, through changes in food intake amount and behavior. Changes in body weight and body composition are similar or greater when animals are maintained on a high fat diet. These data suggest that consumption of a high-fat diet during social stress in the VBS, while it does not appear to affect development of a social hierarchy, enhances the effect that chronic stress has on body composition and may be more representative of what happens in humans in modern society where the typical diet has progressively moved toward higher calorie, high-fat foods.     

硫辛酸改善高脂小鼠氧化应激和慢性炎症的研究

目的:探讨由长期喂饲高脂引发的小鼠机体氧化应激对细胞因子的分泌以及炎症相关基因表达的影响,评价通过添加抗氧化剂硫辛酸对长期氧化应激和慢性炎症的改善作用。方法:30只C57BL/6雄性小鼠,随机分为3组:对照组,高脂模型组(HFD),硫辛酸组(LA)。喂饲10周后测定血浆和脾脏的氧化应激指标。酶联免疫法检测血浆中IFN-γ、IL-4、IL-6、TNF-α、IL-10的含量。荧光定量PCR检测脾脏炎症相关基因C-Jun、NF-κB以及与抗氧化相关基因Mt-1的表达。结果:长期高脂喂饲可导致小鼠免疫器官抗氧化酶活性显著降低,MDA含量显著升高,形成氧化应激。机体长期处于氧化应激态可使血浆IL-4和IL-10显著降低,IFN-γ、IL-6和TNF-α水平显著升高,同时C-Jun和NF-κB炎症反应相关基因表达上调、Mt-1的表达水平下调。添加0.1%LA可有效地防止机体氧化应激的形成。结论:长期高脂喂饲导致的氧化应激可影响机体的免疫功能并诱发慢性炎症反应,LA通过直接清除自由基、恢复氧化还原平衡解除慢性氧化应激从而保护小鼠的免疫功能免受损伤。     

The role of pioglitazone in antioxidant,anti-inflammatory,and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.     

The effect of high‐fat diet on the morphological properties of the forelimb musculature in hypertrophic myostatin null mice

Obesity is a worldwide nutritional disorder affecting body performance, including skeletal muscle. Inhibition of myostatin not only increases the muscle mass but also it reduces body fat accumulation. We examined the effect of high‐fat diet on the phenotypic properties of forelimb muscles from myostatin null mice. Male wild‐type and myostatin null mice were fed on either a normal diet or a high‐fat diet (45% fat) for 10 weeks. Musculus triceps brachii Caput longum; M. triceps brachii Caput laterale; M. triceps brachii Caput mediale; M. extensor carpi ulnaris and M. flexor carpi ulnaris were processed for fiber type composition using immunohistochemistry and morphometric analysis. Although the muscle mass revealed no change under a high‐fat diet, there were morphometric alterations in the absence of myostatin. We show that high‐fat diet reduces the cross‐sectional area of the fast (IIB and IIX) fibers in M. triceps brachii Caput longum and M. triceps brachii Caput laterale of both genotypes. In contrast, increases of fast fiber areas were observed in both M. extensor carpi ulnaris of wild‐type and M. flexor carpi ulnaris of myostatin null mice. Meanwhile, a high‐fat diet increased the area of the fast IIA fibers in wild‐type mice; myostatin null mice display a muscle‐dependent alteration in the area of the same fiber type. The combined high‐fat diet and myostatin deletion shows no effect on the area of slow type I fibers. Although a high‐fat diet causes a reduction in the area of the peripheral IIB fibers in both genotypes, only myostatin null mice show an increase in the area of the central IIB fibers. We provide evidence that a high‐fat diet induces a muscle‐dependent fast to slow myofiber shift in the absence of myostatin. The data suggest that the morphological alterations of muscle fibers under a combined high‐fat diet and myostatin deletion reflect a functional adaptation of the muscle to utilize the high energy intake.     

高脂饮食通过p-AMPK/mTOR信号通路下调小鼠肝细胞自噬水平

目的探讨高脂饮食对小鼠肝细胞自噬的影响并分析其可能机制。方法将C57BL小鼠随机分为2组,每组n=15,给予常规饮食(NC)或高脂饮食(HFD)喂养,8、12和16周后每组随机处死5只小鼠,测体质量、肝质量、内脏脂肪质量;油红(Oil-Red-O)染色测肝脂质沉积;Western blot检测肝脏自噬相关蛋白LC3Ⅱ/LC3Ⅰ、P62和自噬调控信号通路蛋白p-mTOR和p-AMPK的表达。结果 8周时,HFD组小鼠出现腹型肥胖,16周时小鼠体质量、内脏脂肪质量及肝脂滴沉积较NC组明显增加(P<0.01);HFD组8周时肝脏LC3Ⅱ表达较NC组增加(P<0.05);而12及16周肝脏LC3Ⅱ表达较NC组显著降低(P<0.05);P62表达较NC组明显增加(P<0.05)。与NC组相比,HFD组各时间点肝脏p-AMPK表达均减少,而p-mTOR蛋白表达均显著增加。结论高脂饮食初期小鼠肝细胞自噬短暂增加,但长期高脂饮食可导致肝细胞自噬水平显著下调甚至衰竭,肝细胞自噬水平下调与高脂饮食抑制肝细胞p-AMPK表达及增加p-mTOR的活性有关。     

Advanced oxidation protein products in obese women: its relation to insulin resistance and resistin

Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, is thought to take a part in the development of insulin resistance and T2DM. The aim of this study was to characterise the changes in circulating levels of resistin and proinflammatory cytokines tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in diabetic and prediabetic obese patients and to explore their relationship to insulin resistance. Attempts were also made to see whether resistin levels are related to the degree of oxidative stress, as determined by the measurement of advanced oxidation protein products (AOPPs). The study groups consisted of obese diabetic (BMI: 30–42 kg/m², n=28) and prediabetic (BMI: 29–41 kg/m², n=23) women. Fourteen healthy women, with BMI in the range 21.5–25.5 kg/m², were taken as controls. Serum levels of TNF-a, IL-6, resistin, glucose, insulin and AOPPs were measured. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). Diabetic and prediabetic obese patients had increases in serum resistin and TNF-α levels (P<0.01 and P<0.001, respectively). IL-6 levels in diabetic patients were significantly higher than in prediabetics (P<0.05). AOPP levels were also significantly higher in diabetics than prediabetics and controls (P<0.05 and P<0.001, respectively); and positively correlated with blood glucose. Insulin was significantly associated with circulating resistin and TNF-α. The development of insulin resistance may contribute to the elevation of circulating resistin or vice versa. Determination of AOPPs may be helpful for monitoring the impaired glucose metabolism in obesity.     

Irisin与胰岛素抵抗相关疾病

Irisin是由包含Ⅲ型纤连蛋白重复序列基因家族中的一员——含III型纤连蛋白域蛋白5（fibronectin type Ⅲ domain containing protein 5,FNDC5）裂解、释放而产生。肌肉组织是irisin产生的主要组织,而皮下和内脏脂肪组织也可分泌irisin。Irisin既是一种肌细胞因子,亦是一种脂肪因子,是连接肌肉、脂肪与其他组织的重要信使,并在机体能量代谢平衡方面发挥着重要作用,有可能成为治疗肥胖、2型糖尿病及代谢综合征新的潜在靶点。     

Regulation by chronic-mild stress of glucocorticoids, monocyte chemoattractant protein-1 and adiposity in rats fed on a high-fat diet

Stress has been reported as a widespread problem and several studies have linked obesity and inflammation-related diseases. Moreover, the combination of suffering from chronic stress and high energy intake might be related to the onset of some metabolic diseases. To study the possible relationships between stress, inflammatory status and obesity, a chronic-mild stress (CMS) paradigm with a high-fat dietary intake model (Cafeteria diet) was implemented on male Wistar rats for 11 weeks. Stress and dietary intake effects on animal adiposity, serum biochemical as well as glucocorticoids and inflammation markers were all analyzed. As expected, consuming a high-fat diet increased body weight, adiposity and insulin resistance in non-stressed animals. A decrease of total white adipose tissue (WAT) and an increase of fecal glucocorticoids, as well as angiotensinogen, and monocyte chemoattractant protein-1 (MCP-1) expression level in retroperitoneal WAT were found only on control-stressed rats. Regarding the serum MCP-1, a decrease was observed on animals under CMS while being fed Cafeteria diet. Furthermore, 11β-hidroxysteroid dehydrogenase activity, a glucocorticoid and obesity biomarker in the liver, was influenced by high-fat diet intake but not by stress. Finally, statistical analysis showed a strong relation between MCP-1 expression levels in retroperitoneal WAT, fecal corticosterone and total WAT. This trial proved that CMS induced a glucocorticoid-mediated response, which was reduced by the intake of a Cafeteria diet. These findings suggest that a high-fat diet could protect against a stress condition and revealed a different behavior to a stressful environment depending on the nutritional status.     

SHORT syndrome and insulin resistance

We describe a further case of SHORT syndrome. This girl shows nearly all the typical manifestations reported in patients with SHORT syndrome. However, at 14 years she presented with non-ketotic hyperglycemia. At 16¹/₂ years, the diagnosis of diabetes mellitus secondary to severe insulin resistance was made by intravenous insulin challenge. Insulin resistant diabetes mellitus seems to be a new finding in SHORT syndrome, not previously described in this condition. © 1993 Wiley-Liss, Inc.     

Influence of herring (Clupea harengus) and herring fractions on metabolic status in rats fed a high energy diet

Aim: Few dietary studies have looked beyond fish oil to explain the beneficial metabolic effects of a fish‐containing diet. Our aim was to study whether addition of herring, or sub‐fractions of herring, could counteract negative metabolic effects known to be induced by a high‐fat, high‐sugar diet. Methods: Rats were given six different diets: standard pellets; high energy diet with chicken mince (HiE control); high energy diet with herring mince (HiE herring); and high energy diet with chicken mince and either herring oil (HiE herring oil), herring press juice, PJ (HiE PJ) or herring low molecular weight PJ (HiE LMW‐PJ). Factors associated with the metabolic syndrome were measured. Results: There were no differences in energy intake or body weight between the groups, but animals fed high energy diets had a higher body fat content compared with the pellet group, although not statistically significant in all groups. Mesenteric adipocyte size was smaller in the HiE herring oil group compared with the HiE control. Glucose clamp studies showed that, compared with the pellet group, the HiE control and HiE herring diets, but not the HiE herring oil diet, induced insulin resistance. Addition of herring or herring oil to the high energy diet decreased total cholesterol levels, triacylglycerols and the atherogenic index compared with the HiE control group. Conclusions: The results suggest that addition of herring or herring oil counteracts negative effects on blood lipids induced by a high energy diet. The lipid component of herring thus seems to be responsible for these beneficial effects.     

YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance

Objective and design. YKL-40 participates in inflammatory states and vascular processes, which implies that comparison can be made with other inflammatory markers associated with insulin resistance and type 2 diabetes (T2D). In the present study levels of plasma YKL-40 and serum hsCRP were evaluated in patients with T2D. Materials and methods. Patients with T2D and age-matched healthy controls participated in the study. Insulin resistance was estimated using HOMA-IR model. Biochemical parameters were measured in venous blood after a 10 h fast. Results. Patients with T2D were insulin resistant (p < 0.001) and had raised levels of plasma YKL-40 (p < 0.001) and serum hsCRP (p < 0.001). YKL-40 was correlated with HOMA-IR (r = 0.23, p < 0.01), NEFA (r = 0.32, p < 0.001) and triglycerides (r = 0.24, p < 0.05). YKL-40 and hsCRP were not correlated (r = 0.17, p = NS). All participants with hsCRP < 1 mg/l had higher insulin sensitivity (p < 0.05 and p < 0.01, respectively). HsCRP were predicted by HOMA-IR and BMI (r² = 0.48, p < 0.01). Plasma YKL-40 was predicted by HOMA-IR and triglycerides (r² = 0.27, p < 0.01). Conclusions. YKL-40 and hsCRP are elevated in patients with T2D and are related to insulin resistance. No correlation was found between YKL-40 and hsCRP indicating that increased levels of YKL-40 occur independently from elevated plasma hsCRP. Received 17 September 2005; returned for revision 17 October 2005; accepted by I. Ahnfelt-R?nne 18 October 2005     

牙周炎孕鼠影响成年子代脂肪细胞对胰岛素敏感性的研究

目的　探讨牙周炎孕鼠与子代出生低体重的关系以及是否会引起成年子代脂肪细胞产生胰岛素抵抗。 方法　将12只雌性成年Wistar大鼠分成实验性牙周炎组（PD）和对照组（CN），每组各6只。牙周炎组造模7 d后，两组大鼠均与健康雄鼠交配。待孕鼠产后，将雄性子代分为牙周炎子代组（PDO）和对照子代组（CNO），每组18只，分别测新生鼠出生体重和每周体重直至11周。11周后，将所有两组鼠麻醉，分组采血、处死，测血糖、血胰岛素、脂联素、TNF-α、脂肪细胞蛋白激酶B（Akt）丝氨酸磷酸化水平及葡萄糖转运蛋白4（Glut4）的表达水平。 结果　两组新生鼠的出生体重、每周体重和血糖浓度没有统计学差异（P>0.05），PDO组的血胰岛素、脂联素和TNF-α均高于CNO组（P<0.05），胰岛素诱导两组蛋白激酶B丝氨酸磷酸化（p-Akt）水平增加（P<0.05），且胰岛素刺激后PDO组p-Akt水平更低（P<0.05），PDO组Glut4在质膜的表达水平低于CNO组（P<0.05）。 结论　虽然牙周炎孕鼠的子代出生并无低体重，但是可以引起成年子代脂肪细胞产生胰岛素抵抗。     

A preprandial intake pattern in weanling rats ingesting a high fat diet

Six male albino rats were weaned at 16 days and their intake of a high fat liquid diet was subsequently monitored with drinkometers for a 25-day period. Intake increased during growth via an increase in meal size and duration; meal frequency declined and intake rate remained stable. Light-dark differences were found only on the meal frequency measure. Immediately after weaning, there was a significant positive correlation between the duration of the preceding interval and the size of the meal; preprandial correlation. This relationship subsequently declined while the magnitude of the correlation between the meal size and the following interval (postprandial correlation) increased. These results indicate that there is a changeover in the mode of food intake regulation during the early postweaning period.