A Double-Blind Randomized Placebo-Controlled Trial of Sibutramine

Sibutramine is a β-phenethylamine which blocks reuptake of norepinephrine and serotonin. In this clinical study, a group of 173 patients were randomized to treatment with sibutramine at doses of 1, 5, 10, 15, 20 or 30 mg/d and were compared with placebo in a 24-week double-blind trial. There was a dose-dependent reduction in body weight, with doses of 10, 15, 20 and 30 mg being significantly greater than placebo. Weight loss was still continuing in the highest three doses at the end of the study. When drugs were discontinued patients regained weight, as expected. Side effects were generally mild and were most evident in the group treated with the highest dose. These studies suggest that sibutramine may be a valuable new drug for treatment of obesity.     

肠脑轴参与动物食欲的调节机制

肠脑轴是由中枢系统、胃肠道系统共同构成的双向通信系统,其主要通过下丘脑食欲中枢和胃肠道食欲激素来调节动物的食欲,控制其体重,参与能量稳态的调节,是研究动物肥胖和2型糖尿病等代谢疾病的重要轴系。本文综述了肠脑轴对动物食欲、能量平衡和体重的调节作用,展望了肠脑轴在肥胖等相关代谢疾病治疗中的研究前景。     

Food Intake in Prader-Willi Syndrome and Controls with Obesity After Administration of a Benzodiazepine Receptor Agonist

Benzodiazepine receptor (BZR) agonists, used extensively for their anxiolytic effects, have been shown to increase food intake in many mammalian species. Little information, however, is available on the effects of BZR agonists on feeding behaviors of humans. Food intake was evaluated in a 60-minute free-feeding standardized test after the acute administration of the BZR agonist chlordiazepoxide (CDP, Librium; 5 mg or 20 mg) or placebo. Subjects were 12 individuals with the Prader Willi syndrome (PWS), a disorder characterized by extreme hyperphagia and morbid obesity, and 11 controls with obesity. PWS subjects showed the characteristic hyperphagia associated with the appetite disorder, consuming more than six times as many sandwiches as controls with obesity. Results revealed no significant effect of either dose of CDP on the food intake of either group. Serum assays revealed that dose-dependent, clinically effective levels of CDP and active metabolites were achieved. These results suggest that acute administration of the BZR agonist CDP, at the therapeutic levels used, may not increase food intake in populations with obesity. However, the chronic effects of CDP on appetite in human populations still need to be explored.     

The daidzein- and estradiol- induced anorectic action in CCK or leptin receptor deficiency rats

We investigated the effect of daidzein feeding and estradiol treatment on food intake in cholecystokinin-1 receptor (CCK1R) deficiency, leptin receptor (ObRb) deficiency rats and their wild-type rats. These rats underwent an ovariectomy or a sham operation. For the 5 week experiment, each rat was divided in three groups: control, daidzein (150 mg/kg diet), and estradiol (4.2 μg/rat/day) groups. In both CCK1R+ and CCK1R? rats, daidzein feeding and estradiol treatment significantly decreased food intake. Daidzein feeding significantly reduced food intake in ovariectomized ObRb? rats, although not in ObRb+ rats. Estradiol treatment significantly lowered food intake in ovariectomized ObRb+ and ObRb? rats. In the ovariectomized rats, estradiol treatment significantly increases uterine weight, while daidzein feeding did not change it, suggesting that daidzein might have no or weak estrogenic effect in our experiment. These results suggest that CCK1R and ObRb signalings were not essential for the daidzein- and estradiol-induced anorectic action.     

Does a High‐protein Diet Improve Weight Loss in Overweight and Obese Children?

Objective: To evaluate the effect of a high‐protein diet on anthropometry, body composition, subjective appetite, and mood sensations in overweight and obese children attending a residential weight‐loss camp. Research Methods and Procedures: Children (120; BMI, 33.1 ± 5.5 kg/m²; age, 14.2 ± 1.9 years) were randomly assigned to either a standard or high‐protein diet group (15% vs. 22.5% protein, respectively). All children were assessed at baseline and at the end of the camp for anthropometry, body composition, blood pressure, biochemical variables (n = 27), and subjective appetite and mood sensations (n = 50). Results: Attendance at the weight‐loss camp resulted in significant improvements in most measures. Campers lost 5.5 ± 2.9 kg in body weight (p < 0.001) and 3.8 ± 5.4 kg in fat mass (p < 0.001) and reduced their BMI standard deviation score by 0.27 ± 0.1 (p < 0.001) and their waist circumference by 6.6 ± 2.8 cm (p < 0.001). Subjective sensations of hunger increased significantly over the camp duration, but no other changes in appetite or mood were observed. There were no significant differences between the two diets on any physical or subjective measures. Discussion: Weight‐loss camps are effective in assisting children to lose weight and improve on a range of health outcomes, independently of the protein content of the diet. The implications of an increase in hunger associated with weight loss needs to be considered. Further work is warranted to investigate whether higher levels of dietary protein are feasible or effective in longer‐term weight‐loss interventions of this type.     

The 18-kDa Translocator Protein Inhibits Vascular Cell Adhesion Molecule-1 Expression via Inhibition of Mitochondrial Reactive Oxygen Species

Translocator protein 18 kDa (TSPO) is a mitochondrial outer membrane protein and is abundantly expressed in a variety of organ and tissues. To date, the functional role of TSPO on vascular endothelial cell activation has yet to be fully elucidated. In the present study, the phorbol 12-myristate 13-acetate (PMA, 250 nM), an activator of protein kinase C (PKC), was used to induce vascular endothelial activation. Adenoviral TSPO overexpression (10–100 MOI) inhibited PMA-induced vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) expression in a dose dependent manner. PMA-induced VCAM-1 expressions were inhibited by Mito-TEMPO (0.1–0.5 μM), a specific mitochondrial antioxidants, and cyclosporin A (1–5 μM), a mitochondrial permeability transition pore inhibitor, implying on an important role of mitochondrial reactive oxygen species (ROS) on the endothelial activation. Moreover, adenoviral TSPO overexpression inhibited mitochondrial ROS production and manganese superoxide dismutase expression. On contrasts, gene silencing of TSPO with siRNA increased PMA-induced VCAM-1 expression and mitochondrial ROS production. Midazolam (1–50 μM), TSPO ligands, inhibited PMA-induced VCAM-1 and mitochondrial ROS production in endothelial cells. These results suggest that mitochondrial TSPO can inhibit PMA-induced endothelial inflammation via suppression of VCAM-1 and mitochondrial ROS production in endothelial cells.     

Appetite control： why we fail to stop eating even when we are full？

We often eat more than our body needs. We live in an environment where high calorie food is abundant and physical activities are limited. Living in this environment, maintaining healthy bodyweight becomes challenging and obesity becomes a social burden. Why do we continue to eat even after the metabolic needs are satisfied？ Feeding is an ancient behavior essential to survive. Thus the mechanisms to regulate appetite, energy expenditure, and energy storage are well conserved throughout animals. Based on this conservation, we study why we fail to control appetite using a simple genetic model system C. elegans. We have discovered certain genetic components that when misregulated have animals eat more and store more fat. In this review we discuss how these genes work in the appetite control circuit to ultimately understand overall appetite control behavior. We will also briefly discuss how social influence affects feeding regardless of the metabolic status of an animal.     

Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain

Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membrane-associated dehydroepiandrosterone 7alpha-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean KM value of 5.4 micro m, corresponding with the presence of the oxysterol 7alpha-hydroxylase CYP7B1. Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17beta-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high KM value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7alpha-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17beta-hydroxysteroid dehydrogenase activity is significantly higher than in the cerebral neocortex (p < 0.0005). No sex differences were observed. In conclusion, the high levels of CYP7B1 mRNA in brain tissue as well as in a variety of other tissues in combination with the ubiquitous presence of 7alpha-hydroxylase activity in the human temporal lobe led us to assume a neuroprotective function of the enzyme such as regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids, rather than a distinct brain specific function such as neurostimulation or neuromodulation.     

Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor

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血清TSPO、Nesfatin-1、AngⅡ与产后抑郁症的关系分析及其预测价值研究

摘要 目的：探讨血清18 kDa 转位蛋白（TSPO）、摄食抑制因子1（Nesfatin-1）、血管紧张素Ⅱ（AngⅡ）与产后抑郁症（PPD）的关系,并分析其预测PPD的价值。方法：选择2020年2月至2022年6月湖南省妇幼保健院收治的187例产妇,产后3周根据爱丁堡产后抑郁量表（EPDS）评分结果将产妇分为抑郁组（≥13分,31例）和无抑郁组（＜12分,156例）。检测产前、产后3 d血清TSPO、Nesfatin-1、AngⅡ水平,单因素和多因素Logistic回归分析PPD的影响因素,受试者工作特征曲线（ROC）分析TSPO、Nesfatin-1、AngⅡ预测PPD的价值。结果：抑郁组产后血清TSPO水平降低,且低于无抑郁组（P＜0.05）,血清Nesfatin-1、AngⅡ水平增高,且高于无抑郁组（P＜0.05）。单因素分析显示,抑郁组文化程度高中及以下、夫妻关系紧张、家庭经济收入＜5000元/月、分娩方式为剖宫产比例高于无抑郁组（P＜0.05）,新生儿Apgar评分低于无抑郁组（P＜0.05）。多因素Logistic回归分析结果显示低新生儿Apgar评分、文化程度高中及以下、高Nesfatin-1、高AngⅡ、低TSPO是PPD的危险因素（P＜0.05）。TSPO、Nesfatin-1、AngⅡ预测PPD的曲线下面积为0.722、0.736、0.700,联合TSPO、Nesfatin-1、AngⅡ预测PPD的曲线下面积为0.901,高于单独预测。结论：PPD患者血清TSPO水平降低,Nesfatin-1、AngⅡ水平增高,且与PPD的发生有关,联合TSPO、Nesfatin-1、AngⅡ在PPD发生风险的预测方面具有较高价值。     

Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat

Cholecystokinin (CCK) is a peripheral and central mediator of short-term satiety. When given i.p., CCK decreases food intake in previously fasted rats for a period of 30 min. The effect has been previously shown to be abolished by vagotomy and more specifically by severing of vagal sensory rootlets. These studies were designed to determine the effects on rat feeding behavior, and in particular CCK-satiety, of the sensory neurotoxin capsaicin. In neonates, capsaicin selectively and permanently destroys unmyelinated sensory fibers including those in the vagus nerve. Rat neonates were treated with capsaicin, 50 mg/kg or vehicle, and surviving females studied at 8-10 weeks of age. The weights, 24-h food intake, and feeding responses to insulin were the same in adult capsaicin treated (Cap Rx) and vehicle treated (Veh Rx) rats. CCK (8 micrograms/kg i.p.) reduced 30 min food intake 61 +/- 18% in Veh Rx animals (mean +/- S.D., P less than 0.01). In capsaicin denervated animals, CCK also significantly reduced 30 min food intake from 5.09 +/- 1.10 to 3.92 +/- 0.84 g (P less than 0.01), but the mean reduction, 23 +/- 6%, was significantly less than in Veh Rx rats (P less than 10(-4]. A separate group of females, similarly treated as neonates with capsaicin or vehicle, were subjected to bilateral lesioning of the ventromedial hypothalamus. Both Cap Rx and Veh Rx animals gained significantly and equally more than non-lesioned controls. 24 h vagal transport of substance P was reduced 70% in age matched capsaicin treated animals compared to controls. These studies demonstrate that peripheral CCK-satiety is partly mediated by capsaicin sensitive fibers, presumably in the vagus nerve. Substance P is one possible transmitter mediating this reflex. Further conclusions are that active inhibition of an intact peripheral CCK-stimulated reflex arc is not necessary for full expression of central inducers of feeding, e.g., insulin or lesioning of the ventromedial hypothalamus, and that destruction of these fibers does not alter long-term weight regulation in rats receiving a normal diet.     

22R-Hydroxycholesterol protects neuronal cells from beta-amyloid-induced cytotoxicity by binding to beta-amyloid peptide

22R-hydroxycholesterol, a steroid intermediate in the pathway of pregnenolone formation from cholesterol, was found at lower levels in Alzheimer's disease (AD) hippocampus and frontal cortex tissue specimens compared to age-matched controls. beta-Amyloid (Abeta) peptide has been shown to be neurotoxic and its presence in brain has been linked to AD pathology. 22R-hydroxycholesterol was found to protect, in a dose-dependent manner, against Abeta-induced rat sympathetic nerve pheochromocytoma (PC12) and differentiated human Ntera2/D1 teratocarcinoma (NT2N) neuron cell death. Other steroids tested were either inactive or acted on rodent neurons only. The effect of 22R-hydroxycholesterol was found to be stereospecific because its enantiomer 22S-hydroxycholesterol failed to protect the neurons from Abeta-induced cell death. Moreover, the effect of 22R-hydroxycholesterol was specific for Abeta-induced cell death because it did not protect against glutamate-induced neurotoxicity. The neuroprotective effect of 22R-hydroxycholesterol was seen when using Abeta1-42 but not the Abeta25-35 peptide. To investigate the mechanism of action of 22R-hydroxycholesterol we examined the direct binding of this steroid to Abeta using a novel cholesterol-protein binding blot assay. Using this method the direct specific binding, under native conditions, of 22R-hydroxycholesterol to Abeta1-42 and Abeta17-40, but not Abeta25-35, was observed. These data suggest that 22R-hydroxycholesterol binds to Abeta and the formed 22R-hydroxycholesterol/Abeta complex is not toxic to rodent and human neurons. We propose that 22R-hydroxycholesterol offers a new means of neuroprotection against Abeta toxicity by inactivating the peptide.