动脉粥样硬化药物治疗的新靶点——核受体Nur77和类视黄醇X受体

核受体(nuclear receptor,NR)是一类在生物体内广泛分布、配体依赖的转录因子,其成员众多,构成了一个大家族,可分为4大类:类固醇激素受体、甲状腺激素和维生素D受体、孤儿核受体(orphannuclear receptors,ONR)及可被代谢中间产物激活的受体。NR与相应的配体及其辅调节因子相互作用,调控基因的协调表达,从而在机体的生长发育、新陈代谢、细胞分化和凋亡、免疫反应及体内许多生理过程中发挥重要作用[1]。     

Impact of body composition, fat distribution and sustained weight loss on cardiac function in obesity

Background

Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown.

Methods

Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction < 35%), 1091 were elderly (≥ 65 years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics.

Results

All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4 years of follow-up (hazard ratio {HR} associated with age ≥65 years, 1.05; 95% confidence interval {CI}, 0.87-1.27; P = 0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84-1.21; P = 0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10-1.64; P = 0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03-1.50; P = 0.024).

Conclusion

Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients.     

Metabolic remodeling in adipocytes promotes ciliary neurotrophic factor-mediated fat loss in obesity

Obesity is characterized by an expanded adipose tissue mass, and reversing obesity reduces the risk of insulin resistance and cardiovascular disease. Ciliary neurotrophic factor (CNTF) reverses obesity by promoting the preferential loss of white adipose tissue. We evaluated the cellular and molecular mechanisms by which CNTF regulates adiposity. Obese mice fed a high-fat diet were treated with saline or recombinant CNTF for 10 d, and adipose tissue was removed for analysis. Another group fed a high-fat diet was pair fed to CNTF mice. In separate experiments, 3T3-L1 adipocytes were treated with CNTF to examine metabolic responses and signaling. CNTF reduced adipose mass that resulted from reductions in adipocyte area and triglyceride content. CNTF treatment did not affect lipolysis but resulted in decreases in fat esterification and lipogenesis and enhanced fatty acid oxidation. The enhanced fat oxidation was associated with the expression of peroxisome proliferator-activated receptor coactivator-1alpha (PGC1alpha) and nuclear respiratory factor 1 and increases in oxidative phosphorylation subunits and mitochondrial biogenesis as determined by electron microscopy. Studies in cultured adipocytes revealed that CNTF activates p38 MAPK and AMP-activated protein kinase. Inhibiting p38 activation prevented the CNTF-induced increase in PGC1alpha but not AMP-activated protein kinase activation. Diminished food intake with pair feeding induced similar decreases in fat mass, but this was related to increased expression of uncoupling protein 1. We conclude that CNTF reprograms adipose tissue to promote mitochondrial biogenesis, enhancing oxidative capacity and reducing lipogenic capacity, thereby resulting in triglyceride loss.     

The orphan nuclear receptors NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulosa cells: a possible mechanism for repression of aromatase expression upon luteinizing hormone surge

Ovarian granulosa cells play pivotal roles in many aspects of ovary functions including folliculogenesis and steroidogenesis. In response to FSH and LH, the elevation of intracellular cAMP level in granulosa cells leads to activation of multiple ovarian genes. Here, we report findings from a genome-wide study of the cAMP-responsive gene expression profiles in a human granulosa-like tumor cell line, KGN. The study identified 140 genes that are either activated or repressed by 2-fold or greater after stimulation by the adenylyl cyclase activator forskolin. The induction patterns of some cAMP-responsive genes were further analyzed by quantitative real-time PCR. Consistent with previous observations, the LH-responsive genes, such as the nuclear receptor 4A subfamily (NURR1, NGFI-B, and NOR-1), were rapidly but transiently induced, whereas the FSH-responsive gene CYP19 encoding aromatase was induced in a delayed fashion. Interestingly, ectopic expression of NURR1 or NGFI-B severely attenuated the cAMP-responsive activation of the ovary-specific aromatase promoter. Reduction of the endogenous NURR1 or NGFI-B by small interfering RNA significantly elevated aromatase gene expression. The cis-elements responsible for NURR1/NGFI-B-mediated repression were mapped to the minimal aromatase promoter sequence that confers camp responsiveness. Furthermore, the DNA-binding domain of NURR1 was required for the repression. Taken together, these results strongly suggest a causal relationship between the rapid decline of aromatase mRNA and induction of nuclear receptor subfamily 4A expression, which concomitantly occur upon LH surge at the later stages of ovarian follicular development.     

The role of dietary fat in obesity

Current scientific evidence indicates that dietary fat plays a role in weight loss and maintenance. Meta-analyses of intervention trials find that fat-reduced diets cause a 3-4-kg larger weight loss than normal-fat diets. A 10% reduction in dietary fat can cause a 4-5-kg weight loss in individuals with initial body mass index of 30 kg m (-2). Short-term trials show that nonfat dietary components are equally important. Sugar-sweetened beverages promote weight gain, and replacement of energy from fat by sugar-sweetened beverages is counterproductive in diets aimed at weight loss. Protein has been shown to be more satiating than carbohydrate, and fat-reduced diets with a high protein content (20-25% of energy) may increase weight loss significantly. There is little evidence that low-glycemic index foods facilitate weight control. Evidence linking certain fatty acids to body fatness is weak. Monounsaturated fatty acids may even be more fattening than polyunsaturated and saturated fats. No ad libitum dietary intervention study has shown that a normal-fat, high-monounsaturated fatty acid diet is comparable to a low-fat diet in preventing weight gain. Current evidence indicates that the best diet for prevention of weight gain, obesity, type 2 diabetes, and cardiovascular disease is low in fat and sugar-rich beverages and high in carbohydrates, fiber, grains, and protein.     

The obesity paradox and weight loss

Background

An “obesity paradox,” in which overweight and obese individuals with established cardiovascular disease have a better prognosis than normal weight subjects, has been reported in a number of clinical cohorts, but little is known about the effects of weight loss on the obesity paradox and its association with health outcomes.

Methods

Weight was determined in 3834 men at the time of a clinically referred exercise test and again during a clinical evaluation a mean of 7 years later. The associations among weight changes, baseline fitness, and other risk markers with cardiovascular and all-cause mortality were determined by Cox proportional hazards analysis.

Results

During the follow-up period, 314 subjects died (72 of cardiovascular causes). In a multivariate analysis (including baseline weight, weight change, exercise capacity, and cardiovascular disease), weight gain was associated with lower mortality and weight loss was associated with higher mortality (4% higher per pound lost per year, P < .001) compared with stable weight. For all-cause mortality, the relative risks for the no change, weight gain, and weight loss groups were 1.0 (referent), 0.64 (95% confidence interval, 0.50-0.83), and 1.49 (95% confidence interval, 1.17-1.89), respectively (P < .001). Those who died and exhibited weight loss had a significantly higher prevalence of deaths due to cancer and cardiovascular causes.

Conclusion

Weight loss was related to higher mortality and weight gain was related to lower mortality when compared with stable weight. The obesity paradox in our sample is explained in part by a combination of non-volitional weight loss related to occult disease and a protective effect of weight gain.     

Plasminogen activator inhibitor 1 and visceral obesity during pronounced weight loss after bariatric surgery

Background and aimsElevated plasminogen activator inhibitor 1 (PAI-1) concentrations are a hallmark of obesity and are considered to contribute to the development of cardiovascular disease. As adipose tissue constitutes a major source for PAI-1 in obesity, we investigated the individual contribution of subcutaneous and intra-abdominal fat on PAI-1 concentrations during pronounced weight loss after bariatric surgery.Methods and resultsThirty-seven obese adults were examined before and 18 months after surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters and plasma PAI-1 levels by standard methods. BMI was reduced by 9.2 ± 4.9 kg/m², while total fat mass and visceral fat diameter (VFD) decreased by 20.7 ± 11.9 kg and 4.2 ± 2.3 cm, respectively. Concomitantly, PAI-1 levels diminished by 3.2 ± 5.6 ng/ml (all p ≤ 0.015). Change in PAI-1 levels was correlated with change in VFD (r = 0.441, p = 0.008), but not with subcutaneous fat diameter. In stepwise multiple regression analysis change in VFD was an independent predictor of change in PAI-1 concentrations. When adjusted for age and sex or total fat mass associations between PAI-1 and VFD remained significant.ConclusionWe demonstrate that VFD is a major determinant for PAI-1 concentrations during pronounced weight loss after bariatric surgery. Thus, significant reduction of visceral fat mass may contribute to the reduced cardiovascular morbidity and mortality after bariatric surgery by a concomitant decrease in PAI-1 concentrations.     

Energy, substrate and protein metabolism in morbid obesity before, during and after massive weight loss

OBJECTIVE: To investigate the effect of surgically induced weight loss on energy, substrate and protein metabolism of morbidly obese patients. DESIGN: A prospective, clinical intervention study of morbidly obese patients before and after surgical treatment. SUBJECTS: Eight morbidly obese patients (BMI 47.88+/-7.03). METHODS: Total energy expenditure (TEE; doubly labeled water method), sleeping metabolic rate (SMR; respiration chamber), body composition (deuterium oxide component of doubly labeled water), substrate metabolism (48 h dietary records, 48 h urine collection and gaseous exchange in the respiration chamber) and whole body protein turnover (primed-continuous infusion of L-[1-13C]-leucine) were measured before, 3 and 12 months after vertical banded gastroplasty (VBG). RESULTS: The TEE decreased as a result of a decreased SMR (64%) and non-SMR (36%; P=0.001). SMR as a function of fat-free mass (FFM) decreased after weight loss (P<0.05). The physical activity index (PAI), defined as TEE/SMR, was low and was not influenced by weight loss. Protein and carbohydrate oxidation decreased significantly after VBG (P<0.05), although 3 months after VBG protein oxidation did not decrease enough to prevent loss of FFM. The energy used for protein turnover was approximately 24% of SMR and did not change after weight loss. CONCLUSIONS: Compensatory processes that oppose weight loss of morbidly obese patients exist, as demonstrated by the disproportional reduction of SMR, and a low PAI. Protein turnover is not a major contributor to the disproportional reduction of SMR.     

The role of dietary fat in human obesity

Both the amount and quality of dietary fat have been implicated in the pathogenesis of obesity. Adipose tissue fatty and composition, which is known to reflect dietary intake, was sampled in 413 free-living, healthy American males appearing for a routine medical examination. The average age was 46.8 +/- 11.4 years (mean +/- s.d.) and body mass index (BMI)--weight/height--was 25.2 +/- 3.4. The BMI was correlated (P less than 0.01) with known risk factors for cardiovascular disease as follows: total cholesterol (TC) r = 0.18, triglycerides (TG) r = 0.32, low-density lipoprotein cholesterol (LDL-C) r = 0.18, high-density lipoprotein cholesterol (HDL-C) r = -0.24, systolic and diastolic blood pressure (BP) r = 0.30. Underlying patterns which might be related to diet were sought in the distribution of the seven major fatty acids in adipose tissue. Statistical analysis permitted delineation of three factors which were hypothetically related to animals fat intake (F1--monounsaturates), carbohydrate intake (F2--saturates) and vegetable oil intake (F3--polyunsaturates). F1 and F3 together accounted for 12 percent of the variance in BMI while F2 had no influence. Our conclusions are that the variance in BMI is related much more to non-dietary factors than to adipose tissue fatty acid composition and that the nature of dietary fat was not a major distinguishing factor in obesity in this population. There was also no evidence for a high dietary carbohydrate (low fat) intake in the obese.     

Arterial pressure, obesity and fat and alcohol consumption

The baseline data of 2 500 subjects included in the Paris Prospective Study II were used to explore the relationship between the frequency of hypertension and some variables closely linked to the diet. These variables are: body mass, alcohol consumption and the proportion of linoleic acid (C18:2) in the plasma cholesterol esters; the latter variable being used as a marker of dietary intake of linoleic acid. The results show, after adjustment on age and the presence of an antihypertensive treatment, a significant independent relationship between these factors and the frequency of hypertension. The adjusted relative frequency of hypertension is 1, 1.4 and 2.5 in the tertiles of increasing corpulence; 1, 1.2 and 1.7 in the tertiles of increasing alcohol consumption and 1, 0.6 and 0.8 in the tertiles of increasing C18:2. Furthermore, among the 263 subjects belonging simultaneously to the higher tertiles of corpulence and alcohol consumption and to the two lower tertiles of C18:2, the number of hypertensive subjects is 58 (22 p. 100 whereas among the 2 236 remaining subjects, 164 are hypertensives (7 p. 100). These results suggest that hypertension is frequently linked to dietary factors.     

Effects of aerobic exercise and obesity phenotype on abdominal fat reduction in response to weight loss

OBJECTIVE: To test the effects on abdominal fat reduction of adding aerobic exercise training to a diet program and obesity phenotype in response to weight loss. DESIGN: A prospective clinical trial with a 14-week weight-loss intervention design. SETTING AND PARTICIPANTS: In total, 209 overweight and obese women were assigned to four subgroups depending on type of treatment and the subject's obesity phenotype: diet alone (DA) with intra-abdominal fat (IF) obesity (> or =mean IF area), diet plus exercise (DE) with IF obesity, DA with abdominal subcutaneous fat (ASF) obesity (相似文献   

New players in high fat diet-induced obesity: LETM1 and CTMP

Objective

Obesity contributes to insulin resistance and is a risk factor for diabetes. C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) have been reported to influence the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway via the modulation of PKB activity, a key player for insulin signaling. However, it remains unclear whether CTMP and LETM1 are associated with PI3K/PKB signaling in mouse models of obesity.

Materials/Methods

To address this question, we used two different mouse models of obesity, including high-fat diet (HFD)-induced diabetic mice and genetically modified obese mice (ob/ob mice). The levels of insulin-signaling molecules in these mice were determined by immunohistochemical and Western blot analyses. The involvement of CTMP and LETM1 in PI3K/PKB signaling was investigated in HEK293 cells by transient transfection and adenovirus-mediated infection.

Results

We found that the levels of insulin receptor, phosphorylated PKB, and LETM1 were lower and the level of CTMP was higher in the adipose tissue of obese mice on an HFD compared to lean mice on a chow diet. Similar results were obtained in ob/ob mice. In HEK293 cells, the activation of PKB increased the LETM1 level, and inhibition of PKB increased the CTMP level. The overexpression of CTMP suppressed the insulin-induced increase in PKB phosphorylation, which was abrogated by co-overexpression with LETM1.

Conclusion

These results suggest that CTMP and LETM1 may participate in impaired insulin signaling in the adipose tissue of obese mice, raising the possibility that these parameters may serve as new candidate biomarkers or targets in the development of new therapeutic approaches for diabetes.     

Variations in plasma soluble tumour necrosis factor receptors after diet-induced weight loss in obesity

The aim of this study was to investigate the variations in the plasma levels of the soluble tumour necrosis factor receptor type-I (sTNFR-I) and type-II (sTNFR-II) during weight loss which was induced by 3 weeks on a very low calorie diet (3.9+/-0.1 MJ/day), in 17 non-diabetic obese women. Plasma sTNFR-I concentrations decreased significantly after weight loss (p < 0.05), but there was no significant change in plasma sTNFR-II. As the diet was associated with a significant decrease in body fat mass (=2.5 kg), this result supports the emerging concept that adipose tissue can produce significant amounts of sTNFR-I and that this production can be modified by weight loss in human obesity.     

Overweight, obesity and body fat composition in spanish adolescents. The AVENA Study

OBJECTIVE: To describe the prevalence of overweight and obesity in the Spanish adolescent population and its relationship with the socioeconomic status, and to assess their body fat composition and compare these results with previous data from our own country. DESIGN: Cross-sectional multicenter study conducted in five Spanish cities (Granada, Madrid, Murcia, Santander and Zaragoza) in 2000-2002. SUBJECTS: 2,320 adolescents with complete set of anthropometric measurements, 1,192 boys and 1,128 girls. MEASUREMENTS: Body mass index calculated from weight and height measurements, and body fat percentage calculated from skinfold thickness measurements. RESULTS: Overweight + obesity prevalences were 25.69 and 19.13% in boys and girls, respectively. Overweight + obesity prevalence increased in boys from high to medium-low socioeconomic status categories (p = 0.015); meanwhile, there was not a significant effect of socioeconomic status in girls. In males, overweight + obesity prevalence changed from 1985 to 2000-2002 from 13 to 35% and in females from 16 to 32%. The rate of change in overweight + obesity prevalences seems to increase in the last years; from 0.88 (1985 to 1995) to 2.33%/year (1995 to 2000-2002) in males and from 0.5 (1985 to 1995) to 1.83%/year (1995 to 2000-2002) in females. The rate of body fat percentage increase was similar between 1980 and 1995 and between 1995 and 2000-2002: 0.26 and 0.23%/year, respectively, at 13 years of age, and 0.16 and 0.17%/year, respectively, at 14 years of age. CONCLUSION: We observed elevated overweight and obesity prevalences in Spanish adolescents, similar to those observed in other European countries. There is a significant inverse relationship between socioeconomic status and overweight + obesity, but only in boys. The rate of change in overweight prevalence in Spanish adolescents seems to increase, and the rate of increase of body fat percentage seems to be similar as in previous years.