Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells

Mesenchymal hamartomas of the liver are the second most common benign liver tumor of childhood. The experience with this tumor at Egleston's Children Hospital at Emory University from 1989 to 1994 is reviewed. Eight patients presented with abdominal distention or an upper abdominal mass. Six patients presented at a mean age of 8 months, and two patients presented at 17 and 23 years of age, respectively. Four patients displayed normal alpha-fetoprotein levels, whereas one patient had an elevated level. Liver function studies were normal in all patients. Abdominal ultrasonography and CT scans revealed a cystic, septated mass within the liver or on a pedicle in all patients. Five patients had simple excision of the tumor, and two had major hepatic resections. The cysts were multiloculated and lined with cuboidal bile duct epithelium surrounded by stroma containing proliferating bile ducts, blood vessels, and compressed liver tissue with no calcifications. In one patient, some pathologists favored the diagnosis of malignant myxoid fibrous histiocytoma because of similar-appearing stroma. Follow-up (mean, 35 months) revealed one symptomatic recurrence after initial resection was incomplete. There were no other recurrences and no malignant transformations. A septated, noncalcified, cystic hepatic mass in an infant with normal liver function studies and characteristic ultrasound or CT is likely a benign mesenchymal hamartoma that can be cured by total local excision.     

Peroxisome proliferator-activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression

A role for peroxisome proliferator-activated receptors, PPAR gamma and PPAR alpha, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isoforms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPAR gamma or PPAR alpha activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPAR gamma [thiazolidinedione (TZD)] or PPAR alpha (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 at 5 mg/kg x day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3x control levels for UCP-1 and UCP-2, 2.5x control for UCP-3). In contrast, UCP-2 and UCP-3 mRNA levels were not affected in white adipose tissue or skeletal muscle. Chronic (30 days) low-dose (0.3 mg/kg x day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5x control). In contrast, chronic TZD treatment (30 mg/kg x day) suppressed UCP-1 mRNA (>80%) and protein (50%) expression in BAT. This was associated with further induction of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyte, and an increase in the size of the adipocytes. TZD treatment of db/db mice (BRL 49653 at 10 mg/kg x day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPAR alpha is present in BAT, as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-2 mRNA was increased (4x control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPAR gamma activation can induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-intense PPAR gamma activation may cause BAT to assume white adipose tissue-like phenotype with increased UCP-2 levels. PPAR alpha activation in mice is sufficient to induce liver UCP-2 expression.     

Effects of obesity and weight loss on cardiac function and valvular performance

OBJECTIVE: To study the consequences of long-standing obesity on myocardial function and valvular performance and to determine the effects of weight loss on these cardiovascular features. RESEARCH METHODS AND PROCEDURES: We included 41 patients with obesity referred for weight-reducing gastroplasty, 31 patients with obesity who received dietary recommendations, and 43 lean subjects. Body weight and blood pressure were measured, and cardiac function and valvular performance were estimated echocardiographically. Left ventricular ejection fraction was used to assess systolic heart function, and the ratio of transmitral early to atrial (E/A) peak flow velocity was used as an estimate of diastolic filling. All three study groups were investigated at baseline, and the two groups with obesity were re-examined at 1-year follow-up. RESULTS: Patients with obesity had higher blood pressure, greater cardiac output, lower ejection fraction, and reduced E/A ratio, compared with lean subjects (p<0.01). Surgical treatment of obesity led to significant decreases in body weight, whereas body weight remained unchanged in the group treated with dietary recommendations (p<0.001). In the weight loss group, blood pressure and cardiac output decreased and the E/A ratio increased (p<0.001). Left ventricular ejection fraction tended to increase in the weight loss group and decrease in the obese control group (p<0.01). No significant valvular disease was observed in any of the subjects with obesity at baseline or after weight loss. DISCUSSION: We conclude that weight reduction in subjects with obesity is associated with improvements in left ventricular diastolic filling and has favorable effects on left ventricular ejection fraction. Neither obesity nor weight loss seem to promote valvular heart disease.     

Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions

The structurally diverse xenobiotic peroxisome proliferators (PPs) increase the number of peroxisomes per cell and the levels of several enzymes, and cause hepatomegaly, often leading to hepatocarcinogenesis in a species- and tissue-specific manner. The deadlocked problems of the molecular mechanism of PP action and its physiological meanings have begun to be understood through cDNA cloning of a PP-activated receptor (PPAR). PPAR, a member of the steroid/thyroid/vitamin superfamily of nuclear receptors, has isoforms and differentially heterodimerizes with other nuclear receptors, providing potential mechanisms not only for species- and tissue-specific actions but also for diverse actions of PPs. Recent findings related to PPAR are summarized, and its possible role in lipid metabolism and involvement in PP-induced hepatocarcinogenesis are discussed.     

Effects of degree of obesity, age of onset, and weight loss on responsiveness to sensory and external stimuli.

Four experiments tested responsiveness to external and sensory stimuli in human females who differed in degree of overweight and in age of onset of their obesity. A total of 196 overweight Ss, ranging in age from 12–58 yrs and representing both juvenile- and adult-onset obese groups, served as Ss; in Exps I and IV, a total of 14 normal-weight Ss were used as controls. The effects of weight loss on external responsiveness were assessed by testing Ss before and after weight reduction in order to determine the role of energy deficit and deprivation in mediating heightened responsiveness to external cues. There was no significant positive correlation between degree of overweight and degree of external responsiveness. In general, the age of onset of obesity was also not a factor in the degree of externality. Weight loss did not change responses to visual and cognitive cue salience manipulatons in measures of feeding, emotionality, time perception, and short-term recall, while responsiveness to variations in taste palatability increased following weight reduction. While external cue responsiveness does not appear to result from adiposity per se or from deprivation, responsiveness to taste stimuli may reflect these parameters. The role of external and sensory cues in the development and maintenance of obesity is discussed. (42 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential regulation, by MK-801, of dopamine receptor gene expression in rat nigrostriatal and mesocorticolimbic systems

Glutamate agonists have been shown to stimulate striatal dopamine release, but less is known about dopamine-glutamate interactions at the receptor level. We treated rats with 0.3, 1.0, or 3.0 mg/kg of MK-801, an NMDA antagonist, daily for 1 week and, using in situ hybridization, measured dopamine receptor mRNA levels in cortical and subcortical structures. MK-801 caused a significant increase of D1 and D2 mRNA in the dorsal and ventral striatum, a significant decrease of D3 mRNA in the nucleus accumbens, and a significant decrease of D1 mRNA in the limbic cortex. Dopamine autoreceptor expression, reflected by D2 mRNA in the midbrain, was increased in the ventral tegmental area, but not in the substantia nigra. Thus, MK-801 appears to differentially regulate the mesocorticolimbic and nigrostriatal dopamine systems.     

Multihormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: increased responsiveness to glucocorticoids in obesity

The direct role of hormones on leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this hormonal regulation has never been addressed in human visceral fat, although this site plays a determinant role in obesity-linked disorders. In this study, we investigated the hormonal control of ob expression and leptin production in cultured visceral adipose tissue from lean and obese subjects. We more particularly focused on the interactions between glucocorticoids and insulin. We also briefly tackled the role of cAMP, which is still unknown in man. Visceral (and subcutaneous) adipose tissues from eight obese (body mass index, 41 +/- 2 kg/m2) and nine nonobese (24 +/- 1 kg/m2) subjects were sampled during elective abdominal surgery, and explants were cultured for up to 48 h in MEM. The addition of dexamethasone to the medium increased ob gene expression and leptin secretion in a time-dependent manner. Forty-eight hours after dexamethasone (50 nmol/L) addition, the cumulative integrated ob messenger ribonucleic acid (mRNA) and leptin responses were, respectively, approximately 5- and 4-fold higher in obese than in lean subjects. These responses closely correlated with the body mass index. The stimulatory effect of the glucocorticoid was also concentration dependent (EC50 = approximately 10 nmol/L). Although the maximal response was higher in obese than in lean subjects, the EC50 values were roughly similar in both groups. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion. Singularly, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin release. This inhibition was observed in both lean and obese subjects, whereas the expected stimulation of insulin on glucose metabolism and the accumulation of mRNA species for the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate dehydrogenase occurred in lean patients only. This inhibitory effect was already detectable at 10 nmol/L insulin and was also observed in subcutaneous fat. Although a lowering of intracellular cAMP concentrations is involved in some of the effects of insulin on adipose tissue, this cannot account for the present finding, because the addition of cAMP to the medium also decreased ob mRNA and leptin secretion (regardless of whether dexamethasone was present). In conclusion, glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat. This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene and could contribute to the metabolic abnormalities associated with central obesity by para/endocrine actions of hyperleptinemia on adipocytes and liver. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion, and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance.     

Cross-talk between orphan nuclear hormone receptor RZRalpha and peroxisome proliferator-activated receptor alpha in regulation of the peroxisomal hydratase-dehydrogenase gene

The genes encoding the peroxisomal beta-oxidation enzymes enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD) and fatty acyl-CoA oxidase (AOx) are coordinately regulated by peroxisome proliferator-activated receptor alpha (PPARalpha)/9-cis-retinoic acid receptor (RXRalpha) heterodimers that transactivate these genes in a ligand-dependent manner via upstream peroxisome proliferator response elements (PPRE). Here we demonstrate that the monomeric orphan nuclear hormone receptor, RZRalpha, modulates PPARalpha/RXRalpha-dependent transactivation in a response-element dependent manner. Electrophoretic mobility shift analysis showed that RZRalpha bound specifically as a monomer to the HD-PPRE but not the AOx-PPRE. Determinants in the HD-PPRE for binding of RZRalpha were distinct from those required for interaction with PPARalpha/RXRalpha heterodimers. In transient transfections, RZRalpha stimulated ligand-mediated transactivation by PPARalpha from an HD-PPRE luciferase reporter in the absence of exogenously added RXRalpha, but did not affect PPARalpha-dependent transactivation of an AOx-PPRE reporter gene. These data illustrate cross-talk between the RZRalpha and PPARalpha signaling pathways at the level of the HD-PPRE in the regulation of the HD gene and characterize additional factors governing the regulation of peroxisomal beta-oxidation.     

Control of expression of the gene for the arginine transporter Cat-1 in rat liver cells by glucocorticoids and insulin

A general mathematical model for the dynamic behaviour of a single-compartment respiratory system in response to an arbitrary applied inspiratory airway pressure and arbitrary respiratory muscle activity is investigated. The model is used to compute explicit expressions for ventilation and pressure variables of clinical interest for clinician-selected and impedance-determined inputs. The outcome variables include tidal volume, end-expiratory pressure, minute ventilation, mean alveolar pressure, average pleural pressure, as well as the work performed by the ventilator and the respiratory muscles. It is also demonstrated that under suitable conditions, there is a flow reversal that can occur during inspiration.     

Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor gamma 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men

OBJECTIVE: In the white population, an association between oculo(dermal) melanocytosis (ODM) and uveal melanoma is well recognized. However, the lifetime prevalence of uveal melanoma in the ODM population is not known. This study was designed to determine the lifetime prevalence of uveal melanoma among patients with ocular melanocytosis. DESIGN: Fifty-six white patients manifesting ODM with uveal melanoma formed the basis of the study. MAIN OUTCOME MEASURES: Published prevalence rates of ODM and uveal melanoma were used for calculations using Bayes' theorem. RESULTS: The lifetime prevalence of uveal melanoma in white patients with ODM is estimated to be 2.6 x 10(-3). The median age at diagnosis of uveal melanoma in the ODM population was similar to a randomly selected population (60.5 years and 62.5 years, respectively). In the vast majority of patients (90%) with ODM-associated uveal melanoma, the uveal melanoma was diagnosed between the ages of 31 years and 80 years. CONCLUSIONS: One of about 400 patients with ODM followed for life is estimated to develop uveal melanoma. Excessive melanocytes in the uveal tract in ODM may provide the biologic basis for susceptibility to the development of uveal melanoma. Patients with ODM should be monitored ophthalmoscopically, especially during the susceptible period, for the development of uveal melanoma. The authors suggest that a national registry of ODM patients be created and prospective data collected to better assess the risk of developing uveal melanoma.     

Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake

Genetic studies in mice have identified the ob gene product as a potential signaling factor regulating body weight homeostasis and energy balance. It is suggested that modulation of ob gene expression results in changes in body weight and food intake. Glucocorticoids are shown to have important metabolic effects and to modulate food intake and body weight. In order to test the hypothesis that these metabolic effects of glucocorticoids are linked to changes in the expression of the ob gene, ob mRNA levels were evaluated in rats treated with different glucocorticosteroids at catabolic doses and correlated to the kinetics of changes in body weight gain and food intake. Results from time course experiments demonstrate that adipose tissue ob gene expression is rapidly induced by glucocorticosteroids. This induction is followed by a concordant decrease in body weight gain and food consumption. These data suggest that the catabolic effects of corticosteroids on body weight mass and food intake might be mediated by changes in ob expression. Modulation of ob expression may therefore constitute a mechanism through which hormonal, pharmacological, or other factors control body weight homeostasis.     

四环素基因调节系统下小鼠VEGF基因表达效率的测定

为了测定四环素基因调节小鼠模型的有效性和潜在的应用价值,针对各组织中VEGF mRNA表达水平受四环素调节的效率进行了分析.从小鼠不同组织提取总RNA,进行realtime PCR分析,并利用相对定量2-△△CT方法分析这些组织中VEGF基因在mRNA表达水平上的差异,同时观察和统计小鼠组织发育情况.结果表明,转基因小鼠体内各个组织的VEFG mRNA表达水平普遍下降,尤以脂肪和卵巢最为明显.其中心脏VEFG mRNA下降53%,肝脏下降72%,肺下降50%,血小板下降49%,肾脏下降44%,脑下降55%,脂肪下降90%,子宫下降52%,卵巢下降80%.同时VEGF基因表达下降导致小鼠各个相应组织器官的发育大小出现异常.因此,四环素基因调节系统能够有效地调节转基因小鼠各个组织VEGF基因的表达水平.     

Restraint, weight loss, and variability of body weight.

Restrained and unrestrained Ss (n?=?24) were weighed daily for a 6-wk period and again 6 mo later in order to determine whether dietary restraint or relative body weight is the better predictor of weight variability. Restraint was a significantly better predictor of naturally occurring weight fluctuations than was relative body weight. Furthermore, the 2 factors of the Restraint Scale, Concern for Dieting and Weight Fluctuations, were both significant predictors of weight variability. We propose that exaggerated weight fluctuations are not a natural concomitant of higher body weight but possibly the consequence of a cycle of dieting and overeating, which seems to preclude actual weight loss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic loss of glucocorticoids following adrenalectomy down-regulates the expression of glucocorticoid receptor mRNA in the rat forebrain

In the negative feedback model, loss of endogenous glucocorticoids up-regulates the expression of glucocorticoid receptor mRNA. To elucidate further the effect of chronic lack of glucocorticoids on the expression of glucocorticoid receptor mRNA and protein, in situ hybridization and immunohistochemical methods were used to examine the long-term alteration of glucocorticoid receptor mRNA and its immunoreactivity in the forebrain of adrenalectomized rats. Constant lack of glucocorticoids resulted in marked decrease in the expression of glucocorticoid receptor mRNA and disappearance of glucocorticoid receptor immunoreactivity in many forebrain structures. In particular, in the suprapyramidal blade of the hippocampal granule cell layer and cerebral cortex, many cells showed almost no glucocorticoid receptor mRNA signals. These results suggest that long-term loss of endogenous glucocorticoids down-regulates the levels of glucocorticoid receptor mRNA, leading to reduction in the synthesis of glucocorticoid receptors in the rat forebrain. Therefore, the presence of endogenous glucocorticoids is vital to the continued expression of glucocorticoid receptor mRNA.