Activation of the hexosamine signaling pathway in adipose tissue results in decreased serum adiponectin and skeletal muscle insulin resistance

Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and beta-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-D-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNF alpha and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor gamma decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.     

Adipokine levels in Cushing's syndrome; elevated resistin levels in female patients with Cushing's syndrome

BACKGROUND: Cushing's syndrome (CS) is associated with central adiposity, insulin resistance and impaired glucose homeostasis. Adipose tissue is thought to regulates glucose homeostasis via circulating adipokines, such as resistin, leptin and adiponectin, although their role in the insulin resistance associated with CS has not been established. DESIGN: We examined the relationship between insulin resistance and adipokine levels in CS patients. We compared plasma levels of resistin, leptin and adiponectin in 10 women and four men patients with CS, with 14 health subjects matched for age, gender and body mass index. A subgroup of three women and four men with pituitary-dependent CS were re-examined at least 9 months after curative surgery. RESULTS: CS patients had significantly more truncal fat and less lean body mass as assessed by DEXA compared to control subjects. Total cholesterol, triglycerides and insulin resistance, as calculated using the homeostasis model assessment of insulin resistance (HOMA-R), was significantly increased in CS patients. Of the adipokines measured, only resistin was significantly different between female CS patients and female control subjects (5.05 +/- 0.56 vs. 2.91 +/- 0.39 micro g/l, P = 0.015). Curative surgery significantly reduced total body fat and truncal fat, leptin, total and low-density lipoprotein (LDL) cholesterol, glucose and HOMA-R. A reduction in both resistin and adiponectin was also observed but the differences between pre- and post-treatment levels did not achieve statistical significance. CONCLUSION: Here we report for the first time that resistin levels are significantly elevated in CS patients and may be important in the insulin resistance associated with glucocorticoid excess.     

Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging

Energy balance in mammals is modulated by peripheral signals that inform the brain about the magnitude of fat stores, the amount of food in the gastrointestinal tract, and the level of nutrients such as glucose in the circulation. Among these, insulin and leptin are considered adiposity signals involved in the long-term maintenance of fat stores. Here we review the mechanisms of action of leptin and insulin in the hypothalamus and how these mechanisms are altered during aging in rat models. Aged rats are characterized by increased fat mass, central leptin and insulin resistance, and hyperleptinemia. Leptin resistance is manifested by its failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose tissue, and increase energy expenditure. Moreover, leptin and insulin signaling are decreased in hypothalamus from aged rats. Calorie restriction and fasting studies provide controversial data on the cause-effect interrelationship between increased adiposity and development of central leptin resistance. Although in the absence of obesity leptin resistance seems to be a characteristic of aged animals, adiposity could either reinforce it or cause an early onset of this resistance. More studies are necessary to clarify the role of the hypothalamus in the development of age-associated obesity and insulin resistance.     

Changes in glycemia by leptin administration or high- fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis

Resistin is an adipose-derived hormone that has been proposed as a link among obesity, insulin resistance, and diabetes. In agreement with a role of resistin in insulin resistance, the administration of recombinant resistin led to glucose intolerance in mice and impaired insulin action in rat liver. However, the regulation of resistin expression by physiological conditions, hormones, or agents known to modulate insulin sensitivity does not always support the association between resistin and obesity-induced insulin resistance. In the present study we investigated the effects of leptin administration on adipose resistin expression in insulin-resistant and obese ob/ob mice. We show that the expression of resistin mRNA and protein in adipose tissue is lower in ob/ob than in wild-type control mice, in agreement with the reduced adipocyte resistin mRNA level reported in several models of obesity. Leptin administration in ob/ob mice resulted in improvement of insulin sensitivity concomitant with a decrease in resistin gene expression. The lack of effect of leptin on resistin in db/db mice indicated that the leptin inhibitory action on resistin expression requires the long leptin receptor isoform. In addition, we demonstrated that the effect of leptin on resistin expression was centrally mediated. High-fat feeding in C57BL/6J wild-type mice, which is known to induce the development of obesity and insulin resistance, produced an increase in resistin expression. Interestingly, in both ob/ob and high fat-fed mice we obtained a striking positive correlation between glycemia and resistin gene expression. In conclusion, our results demonstrate that leptin decreases resistin expression and suggest that resistin may influence glucose homeostasis.     

Resistance to obesity in Lou/C rats prevents ageing-associated metabolic alterations

Aims/Hypothesis Ageing is associated with metabolic alterations characterised by changes in energy expenditure, obesity, leptin and insulin resistance. The Lou/C rat, an inbred strain of Wistar origin, is presented as both an obesity-resistant rat and a model of healthy ageing.Methods To characterise the mechanisms underlying obesity resistance in Lou/C rat, we measured food intake and energy expenditure by indirect calorimetry at 1, 6, 12, 18, and 24 months of age. Moreover, plasma insulin and leptin concentrations were assessed by radioimmunoassay in Lou/C and Wistar rats throughout their life span.Results Compared to Wistar rats, Lou/C rats presented a higher food intake only at 24 months of age and they had a higher energy expenditure at 6 and 12 months of age (+21% and +14%, respectively). Plasma insulin concentration increased markedly in 18- and 24-month-old Wistar rats, but remained stable during ageing in Lou/C rats. From the age of 6 months, the plasma leptin concentrations in Wistar rats were higher than in Lou/C rats of the same age (four-, seven-, five- and threefold higher at 6, 12, 18, 24 months of age, respectively).Conclusion/interpretation Compared to Wistar rats, Lou/C rats did not develop insulin resistance as confirmed by a higher glucose infusion rate during the hyperinsulinaemic-euglycaemic clamp. These data provide evidence that insulin resistance is associated with the excess of adipose tissue in Wistar rats. Not only Lou/C rats present a higher median life span than Wistar rats (+20%), but they also show a healthy ageing process considering fat accretion and insulin resistance.Abbreviations IGF1-R IGF type 1-receptor     

Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in nonalcoholic fatty liver disease

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.     

雌激素对去卵巢大鼠内脏脂肪细胞脂肪因子表达水平的影响

目的 观察雌激素对去卵巢大鼠内脏脂肪细胞瘦素、脂联素、抵抗素和肿瘤坏死因子-α(TNF-α)表达水平的影响,探讨雌激素对体脂分布的影响机制.方法 6周龄Sprauge-Dawley雌性大鼠30只,采用随机数字表法分成3组:假手术组、去卵巢组和去卵巢+戊酸雌二醇组(OVX+E2组),每组10只.术后1周,OVX+E2组大鼠每天按1 mg/kg体重灌胃戊酸雌二醇水溶液,其他组大鼠灌胃等体积蒸馏水.连续给药12周后,腹主动脉取血,迅速剥离内脏脂肪组织.采用全自动生化分析仪检测血脂、血糖.采用免疫组化染色、实时荧光定量RT-PCR和Western印迹检测脂肪细胞瘦素、脂联素、抵抗素和TNF-α的表达.结果 3组血清瘦素、脂联素和抵抗素水平差异无统计学意义(P均＞0.05),但去卵巢组TNF-α水平显著高于假手术组(F=4.785,P＜0.05).免疫组化显示,与假手术组相比,去卵巢组内脏脂肪组织中瘦素表达明显减弱,而脂联素、抵抗素和TNF-α表达明显增强;与去卵巢组相比,OVX+E2组内脏脂肪组织中瘦素表达明显增强,脂联素、抵抗素和TNF-α表达明显减弱(F =3.712 ～5.198,P均＜0.05).3组内脏脂肪细胞瘦素mRNA和蛋白表达水平差异无统计学意义(P均＞0.05);去卵巢组内脏脂肪细胞脂联素、抵抗素和TNF-α的mRNA和蛋白表达水平显著高于假手术组,而OVX+E2组内脏脂肪细胞脂联素、抵抗素和TNF-α的mRNA和蛋白表达水平显著低于去卵巢组(F=3.175～5.342,P均＜0.05).结论 雌激素可通过下调去卵巢大鼠内脏脂肪细胞脂联素、抵抗素和TNF-α的表达,进而影响去卵巢大鼠体脂再分布.     

Serum resistin level is associated with insulin sensitivity in Japanese patients with type 2 diabetes mellitus

Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiologic features responsible for development of hyperglycemia in type 2 diabetes mellitus. Insulin resistance is often associated with increased adipose tissue mass. To examine which variables influence insulin sensitivity, we compared metabolic parameters, serum resistin, leptin, and adiponectin concentrations to the insulin sensitivity, obtained by frequently sampled intravenous glucose tolerance test using the minimal model analysis, in 113 Japanese patients with type 2 diabetes mellitus. Duration of diabetes, fasting plasma glucose, fasting insulin, homeostasis model assessment of insulin resistance index, and serum resistin concentration were significantly higher in the insulin-resistant subgroup compared with the insulin-sensitive subgroup and correlated with insulin sensitivity. Stepwise regression analysis also identified these parameters as independent regulators of insulin sensitivity. The present study reconfirmed that fasting insulin level or homeostasis model assessment of insulin resistance would be a surrogate measure of insulin resistance and demonstrated that insulin resistance increases progressively after the onset of overt diabetes and that the serum resistin level is associated with insulin sensitivity, suggesting that resistin plays an important role in the development of insulin resistance in Japanese patients with type 2 diabetes mellitus.     

高脂饲养大鼠脂肪组织抵抗素、脂联素及其受体的表达

目的阐明抵抗素、脂联素及其受体在胰岛素抵抗发生中的作用。方法30只Wistar雄性大鼠随机分为对照组和高脂组。用逆转录聚合酶链反应和Southem blot方法分析抵抗素、脂联素和脂联素受体表达的改变。结果高脂组大鼠体重明显增加，空腹血糖、低密度脂蛋白胆固醇、总游离脂肪酸、胰岛素和HOMA胰岛素抵抗指数明显高于对照组，高密度脂蛋白胆固醇明显低于对照组，糖耐量和胰岛素耐量明显下降（P均〈0．01）。高脂组脂肪组织抵抗素和脂联素的表达均明显下降（P〈0．01）；脂联素受体1的表达呈下降趋势，但与对照组相比无统计学意义（P〉0．05）。结论抵抗素和脂联素表达的下降在高脂饮食导致的胰岛素抵抗的发生中起着重要作用，脂联素受体1水平的降低可能是脂联素敏感性降低的重要原因之一。     

Regulation of insulin-stimulated glucose uptake in rat white adipose tissue upon chronic central leptin infusion: effects on adiposity

Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin-dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 μg/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed. We also performed unilateral WAT denervation to clarify the role of the autonomic nervous system in leptin effects on the insulin-stimulated [(3)H]-2-deoxyglucose transport in WAT. Central leptin improved the overall insulin sensitivity but decreased the in vivo insulin action in WAT, including insulin receptor autophosphorylation, insulin receptor substrate-1 tyrosine-phosphorylation, and Akt activation. In this tissue, insulin receptor substrate-1 and glucose transporter 4 mRNA and protein levels were down-regulated after central leptin treatment. Additionally, a remarkable up-regulation of resistin, together with an augmented expression of suppressor of cytokine signaling 3 in WAT, was also observed in leptin-treated rats. As a result, the insulin-stimulated glucose transporter 4 insertion at the plasma membrane and the glucose uptake in WAT were impaired in leptin-treated rats. Finally, denervation of WAT abolished the inhibitory effect of central leptin on glucose transport and decreased suppressor of cytokine signaling 3 and resistin levels in this tissue, suggesting that resistin, in an autocrine/paracrine manner, might be a mediator of central leptin antagonism of insulin action in WAT. We conclude that central leptin, inhibiting the insulin-stimulated glucose uptake in WAT, may regulate glucose availability for triacylglyceride formation and accumulation in this tissue, thereby contributing to the control of adiposity.     

Effects of life-long exercise on circulating free fatty acids and muscle triglyceride content in ageing rats

Regular physical exercise has emerged, together with dietary restriction, as an effective intervention in delaying degenerative diseases and augmenting life span in rodents. The mechanisms involved remain largely unknown, although a beneficial influence on the age-related alteration of insulin sensitivity has been hypothesized. As muscle triglyceride (TG) accumulation is considered a reliable index of muscle insulin resistance, in this study we explored muscle TG content in 23-month-old male Sprague-Dawley rats subjected to life-long training. Plasma glucose, insulin, free fatty acid (FFA) and leptin levels were also measured. Both voluntary running in wheels (RW) and forced training in treadmill (TM) were studied. As RW rats weighed less than controls, a cohort of untrained animals, fed to pair weight (PW) with RW, was added to discriminate the effect of exercise from that of food restriction. Sedentary ad libitum fed rats served as controls. In 23-month-old RW rats, muscle TG content was reduced by 50% with respect to age-matched sedentary controls, while in TM group this reduction was smaller but still highly significant, and occurred independently on the changes in body fat mass. In both the trained rat groups, there was a significant decrease in circulating FFA levels and a trend to reduced insulin levels. In PW rats, muscle TG levels decreased similarly to RW rats, while plasma parameters were less modified. In particular, RW training was more effective than PW in preventing the age-related increase in circulating leptin levels. Our results suggest that voluntary exercise effectively counteracts the development of insulin resistance in the muscles of ageing rats as well as other related changes such as hyperlipacidaemia and compensatory hyperleptinaemia. Forced training or moderate food restriction appear slightly less effective than voluntary exercise in preventing age-dependent alterations in nutrient distribution and/or utilization.     

Divergent regulation of adipose tissue metabolism by calorie restriction and inhibition of growth hormone signaling

Calorie restriction (CR) and a reduced growth hormone (GH) signal affect insulin sensitivity and lifespan in mammals in a similar manner. We investigated the effects of CR and moderate inhibition of GH on glucose-stimulated activation of insulin signaling and the expression of genes related to fat metabolism in white adipose tissue (WAT) in rats. We used 10-month-old male, wild-type (W) Wistar rats, fed ad libitum (AL) or a 30% CR diet from 6 weeks of age, and transgenic (Tg) rats with moderately suppressed GH signaling. Rats were killed 15 min after an intraperitoneal injection of glucose or saline. In control W–AL rats, the levels of serum insulin, phosphorylated (p) insulin receptor (pY-IR), p-Akt, and the expression of glucose transporter (Glut) 4 in the membrane fraction were greater in the glucose-injected group than in the saline-injected group, indicating significant activation of insulin signaling in response to glucose loading. In the W–CR and Tg–AL rats, the serum insulin and pY-IR levels were lower than those in the W–AL rats. The Akt–Glut pathway was up-regulated even after saline-injection. Expression levels of adipogenic and lipogenic genes including PPARγ, adiponectin, and its receptors, were higher in the W–CR rats than in the W–AL and Tg–AL rats. The present findings indicate adipose tissue metabolic profiles specific to CR.     

Innate immunity modulates adipokines in humans

CONTEXT: Chronic inflammation converges in type 2 diabetes and atherosclerosis. Modulation of adipokine signaling by innate immunity in humans is of considerable interest given the role of adipokines in insulin resistance and atherosclerosis. OBJECTIVE: The aim of the study was to examine effects of low-grade endotoxemia, a model of human inflammation, on adipokines in vivo. DESIGN/SETTING: An open-label, placebo-controlled, fixed-sequence clinical study was conducted at a General Clinical Research Center. PATIENTS: There were 20 healthy male (50%) and female volunteers aged 18-40 yr. INTERVENTION: Serial blood sampling and adipose biopsies were performed for 24 h before and after iv bolus endotoxin [lipopolysaccharide (LPS), 3 ng/kg]. MAIN OUTCOME MEASURES: We measured plasma leptin, adiponectin, resistin, soluble leptin receptor, cytokines, insulin, and glucose; distribution of adiponectin among multimeric complexes; whole blood, monocyte and adipose mRNA for adipokines and their receptors. RESULTS: LPS induced fever, blood, and adipose TNF and IL-6 and increased homeostasis model assessment of insulin resistance. These were associated with increases in plasma leptin (from 4.1 +/- 1.1 to 6.1 +/- 1.9 ng/ml in men; 21.1 +/- 4.4 to 27.4 +/- 4.7 ng/ml in women; P < 0.005), doubling of the leptin:soluble leptin receptor ratio, and marked induction of whole blood resistin mRNA (13.7 +/- 7.3-fold; P < 0.001) and plasma resistin (8.5 +/- 2.75 to 43.2 +/- 15.3 ng/ml; P < 0.001). Although total adiponectin levels and low and high molecular weight adiponectin complexes were unaltered by LPS treatment, whole blood mRNA for adiponectin receptors 1 (49%; P < 0.005) and 2 (65%; P < 0.001) was suppressed. CONCLUSIONS: Modulation of adipokine signaling may contribute to the insulin resistant, atherogenic state associated with human inflammatory syndromes. Targeting of individual adipokines or their upstream regulation may prove effective in preventing acute and chronic inflammation-related metabolic complications.     

Impaired central insulin response in aged Wistar rats: role of adiposity

Insulin, like leptin, is considered as a lipostatic signal acting at a central level. Aging and age-associated adiposity have been related to the development of leptin resistance in Wistar rats. In the present article, hypothalamic insulin response during aging has been studied in Wistar rats. Thus, the effects of intracerebroventricular infusion of insulin during a week on food intake and body weight as well as insulin signal transduction after acute intracerebroventricular insulin administration have been studied in 3-, 8-, and 24-month-old rats. To explore the possible role of age-associated adiposity, these experiments were also performed in 8- and 24-month-old rats after 3 months of food restriction to reduce visceral adiposity index to values below those of young animals. Intracerebroventricular administration of insulin during a week was more efficient at reducing food intake and body weight in 3-month-old rats than in 8- and 24-month-old rats. Hypothalamic insulin-stimulated insulin receptor, GSK3, AKT, and p70S6K phosphorylation decreased with aging. Insulin receptor and IRS-2 phosphoserine was increased in 24-month-old rats. Food restriction improved both insulin responsiveness and insulin signaling. These data suggest that Wistar rats develop hypothalamic insulin resistance with aging. This can be explained by alterations of the signal transduction pathway. The fact that food restriction improves central insulin response and signal transduction points to the age-associated adiposity as a key player in the development of central insulin resistance.     

Changes of endocrine function of adipose tissue in anorexia nervosa: comparison of circulating levels versus subcutaneous mRNA expression

OBJECTIVE: To study the influence of chronic malnutrition in patients with anorexia nervosa on endocrine function of adipose tissue on both circulating and subcutaneous fat mRNA expression level. PATIENTS AND DESIGN: A total of 12 patients with anorexia nervosa and 18 normal weight age-matched women underwent anthropometric examination, single blood drawing and subcutaneous adipose tissue biopsy. MEASUREMENTS: Serum concentrations of high-sensitive CRP (hsCRP), leptin, soluble leptin receptor, adiponectin, resistin, interleukin-6 and insulin were measured by Luminex, enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) kits. Subcutaneous adipose tissue mRNA expression of the same adipokines, adiponectin receptors 1 and 2 and immunocompetent cells marker CD68 was measured by real-time polymerase chain reaction (PCR). RESULTS: Decreased body fat content of patients with anorexia nervosa was accompanied by reduced hsCRP, leptin and increased adiponectin and soluble leptin receptor. Resistin, interleukin-6 and insulin levels did not differ from those of the control group. Fat mRNA adiponectin, leptin, interleukin-6 and CD68 expression was reduced, resistin mRNA expression was increased and adiponectin receptor 1 and 2 expression were unchanged as compared to the control group. CONCLUSIONS: Local perturbations in resistin, adiponectin and interleukin-6 mRNA expression in subcutaneous adipose tissue are not reflected by its circulating levels. These changes could be involved in some local metabolic disturbances in subcutaneous adipose tissue of anorexia nervosa patients.     

Effects of prenatal alcohol exposure on glucose tolerance in the rat offspring

Low birth weight in humans predisposes to obesity, cardiovascular diseases, and type 2 diabetes in adult life. Alcohol exposure during pregnancy has been associated with fetal growth restriction. We investigated the effects of prenatal exposure to alcohol on glucose metabolism later in the offspring. Female Sprague Dawley rats were given ethanol (ETOH), 4 g/kg/day by gavage throughout pregnancy. Compared with controls, newborn ETOH rats had decreased body size (5.1 +/- 0.1 v 6.3 +/- 0.1 g, P <.001), plasma insulin (0.44 +/- 0.4 v 0.67 +/- 0.1 ng/mL, P <.05), and leptin mRNA (P <.05), but they had normal beta-cell mass and elevated adipose resistin mRNA and plasma glucose (5.0 +/- 0.5 v 3.6 +/- 0.3 mmol/L, P <.01). Food intake was decreased in ETOH rats during the fourth week of life, and body weight remained decreased compared with controls until a catch-up growth occurred by 7 weeks of life. At 13 weeks of age, body weight and beta-cell mass of ETOH offspring were normal, but plasma glucose and insulin after a glucose challenge were increased compared with controls (P <.05). Adipose leptin and hypothalamic Ob-R mRNA were not different from controls, but resistin was increased (P <.05), and muscle GLUT4 content was decreased (P <.05) in ETOH offspring compared with controls. The data suggest that prenatal alcohol exposure impairs glucose tolerance in the offspring by both inducing insulin resistance and beta-cell dysfunction. The prevailing mechanism in 3-month-old rat offspring appears to be insulin resistance, manifested by glucose intolerance and decreased GLUT4 despite hyperinsulinemia.     

Age-associated loss in adiponectin-activation by caloric restriction: lack of compensation by enhanced inducibility of adiponectin paralogs CTRP2 and CTRP7

Hormonal signals from adipose tissue regulate energy homeostasis but may also be involved in the anti-aging effects of caloric restriction. The purpose of the current study was the investigation of age-dependent effects of caloric restriction on the release of adiponectin, on the expression and activation of adiponectin-related signaling and on parameters of altered insulin sensitivity. In young and in senescent rats, 2 months moderate caloric restriction reduces serum leptin and insulin (young: -50%; old: -30%) suggesting increased insulin sensitivity. However, the same diet enhances serum adiponectin in young (+60%) but not in senescent (+2%, n=NS) rats. Similarly, adiponectin expression (visceral fat) and muscular AdipoR1/2 expression are induced in young rats but not in senescent rats. The locally produced adiponectin paralogs CTRP2/7 are elevated in muscular tissues of old animals (CTRP2 protein: +40%; CTRP7 protein: +50%) and further induced by caloric restriction but this does not result in an increased activation of their downstream target AMPK. Thus, aging is associated with a partial loss of adiponectin inducibility following moderate caloric restriction. This loss is not sufficiently compensated by the locally induced adiponectin paralogs CTRP2/7, although caloric restriction results in increased insulin sensitivity in young and in senescent animals. Thus, the improvement in insulin sensitivity appears to be independent of adiponectin induction by caloric restriction in this model.     

高脂大鼠抵抗素基因的上调表达及与胰岛素、瘦素的相关性

目的 观察SD大鼠高脂饮食状态下脂肪组织中抵抗素的表达及其与胰岛素抵抗以及糖尿病、瘦素等的关系。方法 采用RT—PCR、割胶纯化、基因构建测序的方法，证实为目的片段后，对高脂饮食SD大鼠的脂肪组织进行mRNA抽提，再以此为模板进行半定量RT—PCR扩增及Northern印迹分析。同时检测血清中胰岛素、瘦素水平，并行糖耐量试验、胰岛素释放试验等。结果 (1)成功构建了抵抗素的基因，并经测序证实。(2)与对照组相比，高脂饮食组大鼠脂肪组织中抵抗素表达明显升高，血糖水平、胰岛素水平以及瘦素水平升高。(3)高脂饮食组大鼠在4个月时下丘脑中瘦素受体表达较对照组明显降低。结论 抵抗素表达量的变化与饮食有关，抵抗素可能是胰岛素抵抗、糖尿病发病的一个前期信号，其作用可能与瘦素、瘦素受体有一定关系。