Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.     

肠道菌群在肥胖及相关的代谢性疾病发生发展中的地位和作用

肥胖及相关的代谢性疾病近年来已经成为威胁全球的公共健康问题。越来越多的证据表明,与人类共生的肠道菌群不仅在消化、免疫和抗病方面有不可替代的作用,而且与非传染性的代谢失调相关,特别是其可以通过调节宿主脂肪吸收存储相关的基因,影响后者的能量平衡。因此,肠道菌群可能是在膳食结构变化与人的遗传体质的相互作用下导致肥胖等代谢性疾病发生的一个重要环节。对该环节的深入研究,可能带来代谢性疾病预防和控制策略的革命性的变化。     

Abdominal obesity and metabolic syndrome

Metabolic syndrome is associated with abdominal obesity, blood lipid disorders, inflammation, insulin resistance or full-blown diabetes, and increased risk of developing cardiovascular disease. Proposed criteria for identifying patients with metabolic syndrome have contributed greatly to preventive medicine, but the value of metabolic syndrome as a scientific concept remains controversial. The presence of metabolic syndrome alone cannot predict global cardiovascular disease risk. But abdominal obesity - the most prevalent manifestation of metabolic syndrome - is a marker of 'dysfunctional adipose tissue', and is of central importance in clinical diagnosis. Better risk assessment algorithms are needed to quantify diabetes and cardiovascular disease risk on a global scale.     

肥胖的机制与科学减肥

肥胖问题是严重影响人类生活的现代疾病.其病因极为复杂,涉及遗传、生理、生活方式等多种因素.肥胖可以导致众多的并发病症.控制肥胖的手段有多种选择,运动与合理的饮食是最安全、可行的方法.合理的运动可以有效地控制、调整身体成分,达到健康减肥的目的.综述了肥胖的机制及科学减肥的方法.     

含硫废水的处理与研究进展

介绍了目前国内外对工业含硫废水的常规处理方法以及应用研究情况,对新兴的超临界水氧化法和应用越来越广泛的生物处理法在含硫废水处理的实验研究中所取得的成果,以及工程应用中需解决的问题进行了分析.指出各种物理化学处理方法及生化处理方法的特点和局限性,并探讨了一些新兴含硫废水处理方法的发展前景.     

一个Dirichlet级数的解析性质

在此给出了一个Dirichlet级数,研究了其渐近公式及Res=2附近的阶的估计等若干性质.     

Stromal fibroblasts in cancer initiation and progression

It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.     

Target size regulates calibre and myelination of sympathetic axons

Axons in vertebrate peripheral nerves are ensheathed by Schwann cells. For some axons, this sheath consists of a single layer of glial cell cytoplasm and plasma membranes; for other axons, Schwann cells form multilayered myelin. Whether or not a Schwann cell makes myelin is determined by a signal from the axon, but the nature of this signal is not known. Here I show that sympathetic postganglionic axons, which are normally not myelinated, become myelinated when their calibre is increased as a result of increasing the size of the peripheral target they innervate. This result implies that axon calibre, which is known to be correlated with myelination, is in fact the crucial determinant of whether an axon becomes myelinated. Furthermore, the finding that increasing or decreasing target size causes corresponding increases or decreases in axon size indicates that axon calibre is itself regulated by retrograde signals from peripheral target tissues.     

镍基耐蚀合金特性、进展及其应用

镍基耐蚀合金是一类高性能的耐蚀材料.基于防腐蚀问题,概述了纯镍的性质与耐蚀特性,分析了镍基耐蚀合金与镍铬不锈钢及镍基高温合金的区别与联系.介绍了工程中镍基耐蚀合金的种类及其应用,强调了高性能通用型镍铬钼合金的特征与进展.并结合应用实例,提出应大力发展、开发及应用此类高性能耐蚀材料.     

Medicinal strategies in the treatment of obesity

When prevention fails, medicinal treatment of obesity may become a necessity. Any strategic medicinal development must recognize that obesity is a chronic, stigmatized and costly disease that is increasing in prevalence. Because obesity can rarely be cured, treatment strategies are effective only as long as they are used, and combined therapy may be more effective than monotherapy. For a drug to have significant impact on body weight it must ultimately reduce energy intake, increase energy expenditure, or both. Currently approved drugs for long-term treatment of obesity include sibutramine, which inhibits food intake, and orlistat, which blocks fat digestion.     

Linear ubiquitination prevents inflammation and regulates immune signalling

Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin(cpdm/cpdm)) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling.     

The cargo-binding domain regulates structure and activity of myosin 5

Myosin 5 is a two-headed motor protein that moves cargoes along actin filaments. Its tail ends in paired globular tail domains (GTDs) thought to bind cargo. At nanomolar calcium levels, actin-activated ATPase is low and the molecule is folded. Micromolar calcium concentrations activate ATPase and the molecule unfolds. Here we describe the structure of folded myosin and the GTD's role in regulating activity. Electron microscopy shows that the two heads lie either side of the tail, contacting the GTDs at a lobe of the motor domain (approximately Pro 117-Pro 137) that contains conserved acidic side chains, suggesting ionic interactions between motor domain and GTD. Myosin 5 heavy meromyosin, a constitutively active fragment lacking the GTDs, is inhibited and folded by a dimeric GST-GTD fusion protein. Motility assays reveal that at nanomolar calcium levels heavy meromyosin moves robustly on actin filaments whereas few myosins bind or move. These results combine to show that with no cargo, the GTDs bind in an intramolecular manner to the motor domains, producing an inhibited and compact structure that binds weakly to actin and allows the molecule to recycle towards new cargoes.     

Lifespan: catch-up growth and obesity in male mice

Poor fetal growth is linked with long-term detrimental effects on health in adulthood. Here we investigate whether the lifespan of male mice is affected by their growth rate when they were suckling and find that limiting growth during that period not only increases longevity but also protects against the life-shortening effect of an obesity-inducing diet later on. By contrast, we find that lifespan is considerably shortened if the postnatal period of growth is accelerated to make up for reduced growth in utero, and that, in addition, these mice are susceptible to the adverse effects on longevity of an obesity-inducing diet after weaning.