瘦素（leptin）与肥胖

Obesity is a severely public health problem the whole society faces, and it is correlated closely with many diseases, such as diabetesⅡ, hypertension, coronary heart disease,gallqtone, and so on.Therefore it threatens people‘ s survival quality severely. Obesity is a multiple - factor disease including genetic, metabolic and behavioral factor, and the gene is the main determining factor. With the development of molecular biology technique, people have founded several genes involved in obesity. Among these genes, the research on obese gene is the most profound. The protein leptin is the expression product of the obese gene.This review elucidates the structure, the main biological function, the mechanism of leptin and it‘‘s relationship with obesity.     

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     

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.     

抵抗素（resistin）与2型糖尿病及肥胖症相关研究进展

Resistin, a new hormone found in the year 2001 and secreted by adipocytes, is related to type 2 diabetes and obesity. It brings some hope to solve the medical hamper of insulin resistance. The resistin discovery, molecule structure, function and expression, secretion regulation as well as gene polymorphism are reviewed in the article.     

自噬的免疫调节作用和机制

Autophagy is a major pathway for degradation of cellular components and it contributes to the survival, differentiation, development, and dynamic homeostasis of organisms. Recent studies have demonstrated that autophagic mechanisms act as the effectors of immune systems, pattern recognition receptors and cy-tokines to clean the invasive pathogens in the cells. It was also found that immune systems recognize the invasive pathogens via monitoring the autophagic products. This pathway delivers the cytoplasmic material for lysosomal hydrolysis and presents the antigens to MHC Ⅱ molecules so as to activate the CD4 + T cells. Importantly, autophagy can couple with signaling for stress responses of cells and/or inflammatory responses to function as a defense. This paper reviewed the advance of rapidly developing research field and introduced the molecular mechanisms that autophagy regulates innate and adaptive immunity. These studies will deepen our understanding the mechanisms of immune responses and may provide a novel therapeutic strategy for autophage-associated diseases.     

自噬的免疫调节作用和机制

Autophagy is a major pathway for degradation of cellular components and it contributes to the survival, differentiation, development, and dynamic homeostasis of organisms. Recent studies have demonstrated that autophagic mechanisms act as the effectors of immune systems, pattern recognition receptors and cy-tokines to clean the invasive pathogens in the cells. It was also found that immune systems recognize the invasive pathogens via monitoring the autophagic products. This pathway delivers the cytoplasmic material for lysosomal hydrolysis and presents the antigens to MHC Ⅱ molecules so as to activate the CD4 + T cells. Importantly, autophagy can couple with signaling for stress responses of cells and/or inflammatory responses to function as a defense. This paper reviewed the advance of rapidly developing research field and introduced the molecular mechanisms that autophagy regulates innate and adaptive immunity. These studies will deepen our understanding the mechanisms of immune responses and may provide a novel therapeutic strategy for autophage-associated diseases.     

医学前沿

Auto-aggressive CXCR6 + CD8 T cells cause liver immune pathology in NASHMichael DudekNonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liverdisease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanisticunderstandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features ofhuman NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology.     

High-fat diet and oral infection induced type 2 diabetes and obesity development under different genetic backgrounds

Background : Type 2 diabetes(T2D) is an adult-onset and obese form of diabetes caused by an interplay between genetic, epigenetic, and environmental components.Here, we have assessed a cohort of 11 genetically different collaborative cross(CC)mouse lines comprised of both sexes for T2D and obesity developments in response to oral infection and high-fat diet(HFD) challenges.Methods : Mice were fed with either the HFD or the standard chow diet(control group) for 12 weeks starting at the age of 8 w...     

Autophagy inhibits PDGF-BB-induced calcification in vascular smooth muscle cells

AIM: To investigate the relationship between autophagy and calcification in vascular smooth muscle cells( VSMCs) after plateletderived growth factor( PDGF)-BB stimulation. METHODS: Cultured VSMCs were stimulated with PDGF-BB for different time,the expression of vascular calcification-related proteins and autophagy-related proteins were detected by Western blot. The interaction between Beclin1 and PI3KC3 was detected by co-immunoprecipitation. RESULTS: The expression of BMP2 and ALP showed a trend from decline to rise. ALP slumped at 12 h,and BMP2 slumped at 6 h. Moreover,the expression of Beclin-1 showed a trend from rise to decline,and peaked at 12 h. The conversion of LC3-Ⅰto Ⅱ increased in a time-dependent manner,and peaked at 24 h. The expression of BMP2 and ALP was increased in VSMCs incubated with PDGF-BB and autophagy inhibitor 3-MA,compared with PDGFBB-stimulated VSMCs. Furthermore,the interaction between Beclin1 and PI3KC3 was enhanced at 6 h after PDGF-BB stimulated,peaked at 12 h,and kept in high level at 24 h. Moreover,the phosphorylation level of Beclin1 was enhanced by PDGF-BB stimulation,and peaked at 6 h. CONCLUSION: Our findings demonstrate that PDGF-BB-induced autophagy inhibits VSMC calcification by enhancing Beclin1 phosphorylation and interaction between Beclin1 and PI3KC3.     

Autophagic degradation of mitochondria in white adipose tissue differentiation

Recent work has revealed that autophagy plays a significant role in the process of white adipocyte differentiation. In both in vitro and in vivo model systems, autophagy inactivation by targeted deletion of essential autophagy genes results in alterations in white adipocyte structure. In both models, postdifferentiation cells exhibit atypical morphology, with many small lipid droplets and large numbers of mitochondria, rather than the single large lipid droplet and relatively few mitochondria observed in normal white adipocytes. The role of autophagy as the primary means of the degradation of mitochondria has long been studied, and it is likely that a deficiency in the degradation of mitochondria contributes to the unusual phenotypes observed in mice with autophagy-deficient adipose tissue, including reduced adiposity, resistance to diet-induced obesity, and increased insulin sensitivity. What is not yet known is whether the process of mitochondria-specific autophagy, often referred to as "mitophagy," is specifically induced during adipogenesis or if a general increase in the nonspecific autophagic degradation of mitochondria plays a role in normal adipose differentiation. Despite remaining questions, these findings not only establish the critical role of autophagy in white adipose tissue development, but also suggest that the manipulation of autophagy in adipose tissue may provide novel therapeutic opportunities for metabolic diseases.     

Distinct T cell subsets in adipose tissue are associated with obesity

Adipose tissue inflammation is a driving factor for the development of obesity-associated metabolic disturbances, and a role of adipose tissue T cells in initiating the pro-inflammatory signaling is emerging. However, data on human adipose tissue T cells in obesity are limited, reflected by the lack of phenotypic markers to define tissue-resident T cell subsets. In this study, we performed a deep characterization of T cells in blood and adipose tissue depots using multicolor flow cytometry and RNA sequencing. We identified distinct subsets of T cells associated with obesity expressing the activation markers, CD26 and CCR5, and obesity-specific genes that are potentially engaged in activating pro-inflammatory pathway, including ceramide signaling, autophagy, and IL-6 signaling. These findings increase our knowledge on the heterogeneity of T cells in adipose tissue and on subsets that may play a role in obesity-related pathogenesis.     

多功能蛋白p62调节细胞自噬及相关疾病的研究进展

Sequestosome 1 （p62/SQSTM1）是一种由应激诱导产生的细胞内蛋白并作用于选择性自噬的多功能蛋白.p62包含多种蛋白作用域,可结合聚泛素化蛋白并将其进一步降解,在信号转导过程中发挥重要作用.研究表明,p62参与多种疾病的病理过程,如神经退行性疾病、糖尿病、肥胖甚至是癌症.因而从p62的结构和功能这两方面阐述其在相关疾病中的作用很有必要.     

Autophagy in bone: Self-eating to stay in balance

Autophagy, a major catabolic pathway responsible of the elimination of damaged proteins and organelles, is now recognized as an anti-aging process. In addition to its basal role in cell homeostasis, autophagy is also a stress-responsive mechanism for survival purposes. Here, we review recent literature to highlight the autophagy role in the different bone cell types, i.e., osteoblasts, osteoclasts and osteocytes. We also discuss the effects of autophagy modulators in bone physiology and of bone anabolic compounds in autophagy. Finally, we analyzed studies regarding bone cell autophagy-deficient mouse models to obtain a more general view on how autophagy modulates bone physiology and pathophysiology, particularly during aging.     

细胞自噬与EGFR抑制剂在肿瘤治疗中的研究进展

表皮生长因子受体(EGFR)抑制剂是近些年来肿瘤治疗的新策略。然而,先天性或者获得性耐药问题成为其疗效的一大障碍。自噬,是一种细胞自我消化的过程,并与耐药具有相关性。EGFR的激活能够通过多种信号通路调节自噬过程。EGFR抑制剂能够诱导自噬,然而EGFR诱导自噬的这种特殊作用是双向的。一方面,自噬能够增强EGFR抑制剂的细胞毒性作用,从而成为一种细胞的保护措施;另一方面,EGFR抑制剂治疗后产生的高自噬水平同样能够导致细胞自吞噬性死亡,从而逃脱凋亡,当EGFR抑制剂与一种自噬诱导剂联合应用时可能会产生更显著的治疗作用。因此,调节自噬水平将成为提高肿瘤患者EGFR抑制剂治疗效果的可行之举。     

Heat shock protein 72 enhances autophagy as a protective mechanism in lipopolysaccharide-induced peritonitis in rats

Peritoneal dialysis-related peritonitis causes the denudation of mesothelial cells and, ultimately, membrane integrity alterations and peritoneal dysfunction. Because heat shock protein 72 (HSP72) confers protection against apoptosis and because autophagy mediates survival in response to cellular stresses, we examined whether autophagy contributes to HSP72-mediated cytoprotection in lipopolysaccharide (LPS)-induced peritonitis. Exposure of cultured peritoneal mesothelial cells to LPS resulted first in autophagy and later, apoptosis. Inhibition of autophagy by 3-methyladenine or Beclin-1 small-interfering RNA sensitized cells to apoptosis and abolished the antiapoptotic effect of HSP72, suggesting that autophagy activation acts as a prosurvival mechanism. Overexpression of HSP72 augmented autophagy through c-Jun N-terminal kinase (JNK) phosphorylation and Beclin-1 up-regulation. Suppression of JNK activity reversed HSP72-mediated Beclin-1 up-regulation and autophagy, indicating that HSP72-mediated autophagy is JNK dependent. In a rat model of LPS-associated peritonitis, autophagy occurred before apoptosis in peritoneum. Up-regulation of HSP72 by geranylgeranylacetone increased autophagy, inhibited apoptosis, and attenuated peritoneal injury, and these effects were blunted by down-regulation of HSP72 with quercetin. Additionally, blocking autophagy by chloroquine promoted apoptosis and aggravated LPS-associated peritoneal dysfunction. Thus, HSP72 protects peritoneum from LPS-induced mesothelial cells injury, at least in part by enhancing JNK activation-dependent autophagy and inhibiting apoptosis. These findings imply that HSP72 induction might be a potential therapy for peritonitis.     

Vitamin E inhibits activated chaperone-mediated autophagy in rats with status epilepticus

Seizures and status epilepticus induce an excessive production of reactive oxygen species leading to oxidative stress. Vitamin E, a classic antioxidant, has a neuroprotective effect on rats with seizures by regulating reactive oxygen species production. The activity of chaperone-mediated autophagy, a selective pathway for the degradation of cytosolic proteins in lysosomes, is enhanced during oxidative stress. Whether chaperone-mediated autophagy is induced during status epilepticus is not established. To address this problem, we used pilocarpine to elicit status epilepticus in rats. Lysosome-associated membrane protein 2a was used to estimate chaperone-mediated autophagy. We showed that compared to control animals, lysosome-associated membrane protein 2a at lysosomal membranes increased significantly in rats at 8 h, 16 h, and 24 h after induction of status epilepticus, which directly correlated with chaperone-mediated autophagy activity. Since reactive oxygen species are believed to be important in the pathogenesis of status epilepticus and are essential for the process of chaperone-mediated autophagy, we also sought to determine if pretreatment with vitamin E reduced chaperone-mediated autophagy. Pretreatment with vitamin E reduced oxidative stress and partially inhibited chaperone-mediated autophagy in brain at 24 h after status epilepticus versus vehicle. Taken together, these data show that chaperone-mediated autophagy is increased in rats with pilocarpine-induced status epilepticus through upregulation of de novo synthesis of lysosome-associated membrane protein 2a. Antioxidants such as vitamin E may partially inhibit activated chaperone-mediated autophagy.     

The dynamic nature of autophagy in cancer

Macroautophagy (referred to hereafter as autophagy) is a highly regulated cellular process that serves to remove damaged proteins and organelles from the cell. Autophagy contributes to an array of normal and pathological processes, and has recently emerged as a key regulator of multiple aspects of cancer biology. The role of autophagy in cancer is complex and is likely dependent on tumor type, stage, and genetic context. This complexity is illustrated by the identification of settings where autophagy acts potently to either promote or inhibit tumorigenesis. In this review, I discuss the underlying basis for these opposing functions and propose a model suggesting a dynamic role for autophagy in malignancy. Collectively, the data point to autophagy as serving as a barrier to limit tumor initiation. Once neoplastic lesions are established, it appears that adaptive changes occur that now result in positive roles for autophagy in malignant progression and in subsequent tumor maintenance. Remarkably, constitutive activation of autophagy is critical for continued growth of some tumors, serving to both reduce oxidative stress and provide key intermediates to sustain cell metabolism. Autophagy is also induced in response to cancer therapies where it can function as a survival mechanism that limits drug efficacy. These findings have inspired significant interest in applying anti-autophagy therapies as an entirely new approach to cancer treatment. It is now apparent that aberrant control of autophagy is among the key hallmarks of cancer. While much needs to be learned about the regulation and context-dependent biological functions of autophagy, it seems clear that modulation of this process will be an attractive avenue for future cancer therapeutic approaches.     

ERK and Akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells

Advanced glycation end products (AGEs) play an important role in the proliferation of vascular smooth muscle cells (VSMCs) and accelerate atherosclerosis in diabetic patients. Autophagy, a life-sustaining process, is stimulated in atherosclerotic plaques by oxidized lipids, inflammation and metabolic stress conditions. In our studies, we utilized MTT assays to show that autophagy is involved in AGE-induced proliferation of VSMCs. Furthermore, treatment with AGEs (100 μg/ml) could induce autophagy in a time- and dose-dependent manner in rat aortic VSMCs. These results were further substantiated by electron microscopy and immunofluorescence imaging. Treatment with AGEs activated ERK, JNK and p38/MAPK, but inhibited Akt. Pretreatment with an ERK inhibitor and an Akt activator inhibited AGE-induced autophagy, demonstrating that AGEs induce autophagy in VSMCs through the ERK and Akt signaling pathways. In addition, RNA interference of RAGE decreased autophagy, indicating that RAGE is pivotal in the process of AGE-induced autophagy. Therefore, AGE-induced autophagy contributes to the process of AGE-induced proliferation of VSMCs, which is related to atherosclerosis in diabetes.