Metabolic surgery:present and future

Several articles in this issue of the Journal cover a broad range of the new concepts of metabolic surgery,the mechanisms that leads to sustained metabolic syndrome remission,the new surgical procedures,and the perspective of surgeons and endocrinologists.Obesity is a global health concern.Health surveys from 2005 revealed that the number of overweight and obese individuals in China were 200 million and[1]60 million,respectively.The rising prevalence of obesity is causing a major health burden in terms of     

眼白化病1型的分子病理生理基础

Ocular albinism type 1 (OA1), the most form of the ocular albinism, is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina, photophobia, strabismus and nystagmus. The OA1 gene is located on chromosome Xp22.32 and the coding sequence is divided into nine exons. The OA1 gene codes for a 404 amino acid protein thought to be a melanosomal transmembrane glycoprotein. The OA1 protein is similar to the G protein-coupled receptors, but it‘s exact function is not clear. There are many mutations and deletions of the OA1 gene have been found.     

自噬在肥胖中的研究进展

Obesity is a harmful nutritional metabolic disorder to human health. Autophagy is a catabolic mechanism whereby cells degrade intracellular substances. Recent studies show that autophagy was closely correlated with insulin resistance, fat composing, and lipid droplet and triglyceride accumulation. Here, we review the association between autophagy and obesity, which may provide theoretical and experimental evidence for prevention of obesity and related diseases.     

Leptin Signaling Protects NK Cells from Apoptosis During Development in Mouse Bone Marrow

Increasing evidence indicates a role of leptin in immune response, but it remains largely unclear whether leptin signaling is involved in regulating NK cell development in the bone marrow （BM）. In this study, we have characterized NK cell differentiation and maturation in the BM of leptin-receptor deficient db/db mice at a prediabetic stage. Although the BM cellularity was similar to the control value, the total number of NK cells was severely reduced in mutant mice. Flow cytometric analysis of db/db BM cells revealed significantly decreased frequencies of developing NK cells at various stages of differentiation. BM db/db NK cells displayed markedly increased apoptosis but maintained normal cell cycling status and proliferative capacity. Moreover, recombinant leptin could significantly enhance the survival of NK cells from wild-type mice in cultures. Further examination on NK cell functional activity showed that db/db NK cells exhibited normal intrinsic cytotoxicity with significantly increased IL-10 production. Taken together, our findings suggest that leptin signaling regulates NK cell development via enhancing the survival of immature NK cells in mouse BM.     

HDAC9 Gene Linked to Heart Disease and Diabetes

Last month, cardiac researchers at the University of Cincinnati discovered a unique gene associated with heart disease and diabetes. This gene, the HDAC9, was shown to prevent the effects of obesity. The HDAC9 gene codes for the enzyme Histone Deacetylase 9, which belongs to a class of enzymes responsible for controlling DNA expression. Removing this enzyme from the cellular atmosphere     

阿尔茨海默病中Aβ损伤线粒体的研究进展

The β-amyloid protein (Aβ) has long been considered to associate with Alzheimers disease (AD). In addition, groups of evidence show that the soluble intracellular Aβ plays an important role in the disease development. The mitochondrial dysfunction induced by Aβ accumulation is a main pathologic process in early stage of AD. Matured Aβ is imported into the mitochondria through an unclear route. Once inside the mitochondria, Aβ is able to interact with a number of targets, including amyloid-binding alcohol dehydrogenase (ABAD) and cyclophilin D (CypD), which is a component of the mitochondrial permeability transition pore. Interference with the normal functions of these proteins results in mitochondrial injury, such as energy dyshomeostasis, production of reactive oxygen species, membrane permeability alteration and so on. This review explores the Aβ generation and location in mitochondria. The mitochondrial injury induced by the interaction between Aβ and its targets are also discussed.     

nNOS-mediated protein-protein interactions: promising targets for treating neurological and neuropsychiatric disorders

Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people.Nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS)in the brain.Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders,including stroke,depression and anxiety disorders,posttraumatic stress disorder,Parkinson’s disease,Alzheimer’s disease,chronic pain,and drug addiction.Due to critical roles of nNOS in learning and memory and synaptic plasticity,direct inhibition of nNOS may cause severe side effects.Importantly,interactions of several proteins,including post-synaptic density 95(PSD-95),carboxyterminal PDZ ligand of nNOS(CAPON)and serotonin transporter(SERT),with the PSD/Disc-large/ZO-1 homologous(PDZ)domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain.Therefore,it will be a preferable means to interfere with nNOS-mediated proteinprotein interactions(PPIs),which do not lead to undesirable effects.Herein,we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders,and the discovery of drugs targeting the PPIs,which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.     

Hepatic transcriptome signatures in mice and humans with nonalcoholic fatty liver disease

Background : Nonalcoholic fatty liver disease(NAFLD) is the main reason for cirrhosis and hepatocellular carcinoma. As a starting point for NAFLD, the treatment of nonalcoholic fatty liver(NAFL) is receiving increasing attention. Mice fed a high-fat diet(HFD) and hereditary leptin deficiency(ob/ob) mice are important NAFL animal models. However, the comparison of these mouse models with human NAFL is still unclear.Methods : In this study, HFD-fed mice and ob/ob mice were used as NAFL animal mode...     

抵抗素在肥胖及糖尿病中的作用

Increased evidences indicate that resistin is a new hormone secreted from adipose tissue,it is reported to be an important signal molecule linking between obesity, insulin resistance and type 2 diabetes.Many factors can affect the gene expression of resistin. However, the detailed function of resistin still remainsmys terious and much work needs to be undertaken.     

17Beta-estradiol Promotes Proliferation of Rat Synthetic Vascular Smooth Muscle Cells by Up-regulating Cyclin D_1

1 IntroductionCardiovascular disease (CVD) is the leading cause of morbidity and mortality in women after 50 years of age in most developed countries. Estrogen deficiency plays a key role in causing CVD in women. The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall, and the proliferation of vascular smooth muscle cells (VSMC) plays a major role as an initiating event of atherosclerosis. A previous study by us in cooperation with Campble‘s group~([1])...     

瘦素与结直肠癌的关系

肥胖是结直肠癌发病的危险因素,瘦素是ob基因的表达产物,主要来源于脂肪细胞,是重要的脂肪因子之一,被认为是肥胖和结直肠癌之间联系的重要角色。近年来对瘦素在结直肠癌的形成和进展中的作用及机制的研究对结直肠癌的诊断和治疗具有重要意义。     

Effects of Diet-Induced Mild Obesity on Airway Hyperreactivity and Lung Inflammation in Mice

Purpose

Obesity has been suggested to be linked to asthma. However, it is not yet known whether obesity directly leads to airway hyperreactivity (AHR) or obesity-induced airway inflammation associated with asthma. We investigated obesity-related changes in adipokines, AHR, and lung inflammation in a murine model of asthma and obesity.

Materials and Methods

We developed mouse models of chronic asthma via ovalbumin (OVA)-challenge and of obesity by feeding a high-fat diet, and then performed the methacholine bronchial provocation test, and real-time PCR for leptin, leptin receptor, adiponectin, adiponectin receptor (adipor1 and 2), vascular endothelial growth factor (VEGF), transforming growth factor (TGF) β, and tumor necrosis factor (TNF) α in lung tissue. We also measured cell counts in bronchoalveolar lavage fluid.

Results

Both obese and lean mice chronically exposed to OVA developed eosinophilic lung inflammation and AHR to methacholine. However, obese mice without OVA challenge did not develop AHR or eosinophilic inflammation in lung tissue. In obese mice, lung mRNA expressions of leptin, leptin receptor, VEGF, TGF, and TNF were enhanced, and adipor1 and 2 expressions were decreased compared to mice in the control group. On the other hand, there were no differences between obese mice with or without OVA challenge.

Conclusion

Diet-induced mild obesity may not augment AHR or eosinophilic lung inflammation in asthma.     

The effect of obesity on inflammatory cytokine and leptin production following acute mental stress

Obesity may contribute to cardiovascular disease (CVD) risk by eliciting chronic systemic inflammation and impairing the immune response to additional stressors. There has been little assessment of the effect of obesity on psychological stress, an independent risk factor for CVD. Therefore, it was of interest to examine interleukin‐6, tumor necrosis factor‐α, interleukin‐1β (IL‐1β), interleukin‐1 receptor antagonist (IL‐1Ra), and leptin following an acute mental stress task in nonobese and obese males. Twenty college‐aged males (21.3 ± 0.56 years) volunteered to participate in a 20‐min Stroop color‐word and mirror‐tracing task. Subjects were recruited for obese (body mass index: BMI > 30) and nonobese (BMI < 25) groups, and blood samples were collected for enzyme‐linked immunosorbent assay analysis. The acute mental stress task elicited an increase in heart rate, catecholamines, and IL‐1β in all subjects. Additionally, acute mental stress increased cortisol concentrations in the nonobese group. There was a significant reduction in leptin in obese subjects 30 min posttask compared with a decrease in nonobese subjects 120 min posttask. Interestingly, the relationship between the percent change in leptin and IL‐1Ra at 120 min posttask in response to an acute mental stress task was only observed in nonobese individuals. This is the first study to suggest that adiposity in males may impact leptin and inflammatory signaling mechanisms following acute mental stress.     

Factors promoting and ameliorating the development of obesity

Obesity develops when energy intake exceeds expenditure. A constant neural, metabolic and hormonal "conversation" between the brain and periphery underlies the defense of a given level of adiposity. For the majority of humans, obesity becomes a permanent condition once it develops, possibly because of irreversible changes in the distributed network of specialized "metabolic sensing" neurons which regulate energy intake, expenditure and storage. Plasma leptin and insulin are catabolic hormones whose levels reflect the amount of adiposity and act as signal to metabolic sensing neurons. Obesity-prone individuals have an inborn reduction in their catabolic responses to glucose, leptin and insulin. These raised metabolic and hormonal sensing thresholds precede the development of obesity and predispose individuals to become and remain obese on energy dense diets. High fat diets exacerbate this problem by independently inhibiting central insulin and leptin signaling. In addition, intake of highly palatable diets overrides the homeostatic controls of ingestion because it is regulated by neural systems mediating reward and motivation. The genetic predisposition to become obese is accentuated in offspring of mothers who are obese or nutritionally deprived during gestation and/or lactation or by overfeeding during the early postnatal period. On the other hand, chronic stress and illness can both reduce adiposity, as does gastric bypass surgery. However, for chronic obesity treatment, both exercise and pharmacotherapy help but both must be continued chronically to provide sustained lowering of body weight in obese subjects. Given the permanent upward resetting of body weight set-point that occurs when genetically predisposed individuals become obese, identification of factors that prevent the development of obesity is likely to be the most successful means of ameliorating the current obesity epidemic.     

Leptin--the fat controller

Obesity is a common health disorder in humans and is inherited genetically. Though several theories have been proposed in the past to understand the mechanisms underlying the control of obesity, the recent discovery of leptin (OB) has made the obesity research interesting. OB, a product of ob gene is a 16 KD protein, secreted by the adipocytes. It acts through its receptor (OB-R), which is a product of db gene. ob and OB-R in conjunction with neuropeptide Y, melanocyte stimulating hormone and melanocortin-4 receptor have been found to control adiposity. Though several issues pertaining to ob need to be addressed, it is anticipated that future treatment of obesity may depend on our understanding of the action(s) of leptin and its associated molecules and receptors.     

Chronic inflammation in psoriasis and obesity: implications for therapy

A recent study has shown an indisputable relationship between psoriasis and obesity. Obesity leads to a higher risk in developing psoriasis and a poorer long-term clinical outcome of psoriasis. Furthermore, loosing weight may improve the psoriasis. A network of pro-inflammatory cytokines (especially tumour necrosis factor alpha (TNF-alpha)) is believed to play an important role in the pathophysiology of both obesity and psoriasis. The chronic low-level inflammation- as seen in obesity--may contribute to the extent of psoriatic lesions in obese patients. TNF-alpha in obesity is presumed to be derived from inflammatory cells (macrophages) in the adipose tissue and in psoriasis from activated T cells. Several drugs, such as peroxisome proliferator activated receptor (PPAR)-gamma agonists and TNF-alpha blocking agents, that target the pro-inflammatory pathways involved in both psoriasis and obesity have proven their benefit in the treatment of these entities. Furthermore, changes in levels of metabolic hormones as ghrelin and leptin in obesity may also play a role in the pathogenesis of deterioration of psoriasis by their potency to release pro-inflammatory mediators (e.g. interleukin (IL) 6 and TNF-alpha). We hypothesize that the treatment of obese psoriasis patient could be focused on reducing the obesity-induced inflammation. Reducing this obesity-induced inflammation may finally lead to a better clinical outcome. Weight loss could lead to a less inflammatory state by reducing concentrations of TNF-alpha, IL-6, leptin and improving insulin sensitivity.     

Improving reproductive performance in overweight/obese women with effective weight management

Obesity and overweight are common conditions in the developed countries and they carry many health consequences, including some reproductive disorders. There is a very high prevalence of obese women in the infertile population and many studies have highlighted the link between obesity and infertility. A large proportion of infertile women have polycystic ovary syndrome (PCOS) which is also linked with increased risk of obesity and other metabolic anomalies. The association between obesity and/or PCOS and hyperinsulinaemia, hyper androgenism and abnormal secretion of other hormones, such as leptin, underlies many reproductive disorders observed in this population. It has been demonstrated that weight loss can improve the fertility of obese women through the recovery of spontaneous ovulation, whereas others will have improved response to ovarian stimulation in infertility treatment. Therefore, it is proposed that following the initial assessment of infertility and body mass index or other measurement of obesity, various weight management interventions, including diet, exercise or pharmacotherapeutic approaches, should be considered for overweight and obese infertile women.     

Diet‐induced obesity disrupts ductal development in the mammary glands of nonpregnant mice

Mammary glands develop postnatally in response to the hypothalamic‐pituitary‐gonadal axis. Obesity‐induced changes in the local environment, however, retard mammary gland development during late pregnancy and lactation. To clarify the effects of obesity on fundamental duct development, we compared the mammary glands of nulliparous nonpregnant obese mice fed a high‐fat diet with those of lean mice fed a normal diet. Obese mice had enlarged mammary glands, reflecting fat pad size, whereas the ducts in obese mice showed a less dense distribution with less frequent branching. Additionally, the ducts were surrounded by thick collagen layers, and were incompletely lined with myoepithelium. Because leptin receptors were localized in the epithelium region and leptin that was highly expressed in the obese glands suppressed mammary epithelial cell proliferation in vitro, the present results suggest that obesity disrupts mammary ductal development, possibly by remodeling the mammary microenvironment and promoting the expression of such paracrine factors as leptin. Developmental Dynamics 238:1092–1099, 2009. © 2009 Wiley‐Liss, Inc.     

Lipopolysaccharide‐binding protein and leptin are associated with stress‐induced interleukin‐6 cytokine expression ex vivo in obesity

Obesity is associated with enhanced inflammation and mental stress, but limited information has addressed the potential additive effect of psychological stress on obesity‐associated inflammation. This study examined whether obese subjects would elicit a greater host immune response (IL‐6 mRNA and cytokine) to lipopolysaccharide (LPS) in response to mental stress. Blood samples for LPS‐stimulated IL‐6 mRNA and cytokine were collected prior to and following mental stress. Results showed that obese subjects elicited a greater LPS‐induced IL‐6 along with its mRNA expression following mental stress compared to normal‐weight subjects. Stress‐induced IL‐6 cytokine response to LPS was correlated with the baseline levels of plasma LPS binding protein (LBP) and leptin. These findings are consistent with the idea that endogenous inflammatory agents (e.g., LBP and leptin), often elevated with obesity, enhance inflammatory responses to psychological stress.