Metabolic consequences of ENPP1 overexpression in adipose tissue

Ectonucleotide pyrophosphate phosphodiesterase (ENPP1) has been shown to negatively modulate insulin receptor and to induce cellular insulin resistance when overexpressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is overexpressed in multiple tissues of transgenic models and attributed largely to tissue insulin resistance induced in skeletal muscle and liver. Another key tissue in regulating glucose and lipid metabolism is adipose tissue (AT). Interestingly, obese patients with insulin resistance have been reported to have increased AT ENPP1 expression. However, the specific effects of ENPP1 in AT have not been studied. To better understand the specific role of AT ENPP1 on systemic metabolism, we have created a transgenic mouse model (C57/Bl6 background) with targeted overexpression of human ENPP1 in adipocytes, using aP2 promoter in the transgene construct (AdiposeENPP1-TG). Using either regular chow or pair-feeding protocol with 60% fat diet, we compared body fat content and distribution and insulin signaling in adipose, muscle, and liver tissues of AdiposeENPP1-TG and wild-type (WT) siblings. We also compared response to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Our results show no changes in Adipose ENPP1-TG mice fed a regular chow diet. After high-fat diet with pair-feeding protocol, AdiposeENPP1-TG and WT mice had similar weights. However, AdiposeENPP1-TG mice developed fatty liver in association with changes in AT characterized by smaller adipocyte size and decreased phosphorylation of insulin receptor Tyr(1361) and Akt Ser(473). These changes in AT function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose, and insulin during IPGTT and decreased glucose suppression during ITT. Thus, our results show that, in the presence of a high-fat diet, ENPP1 overexpression in adipocytes induces fatty liver, hyperlipidemia, and dysglycemia, thus recapitulating key manifestations of the metabolic syndrome.     

基于卫星追踪探讨黄河流域自然保护区对3种水鸟栖息地的保护现状

自然保护区是生物多样性保护的重要形式, 对于迁徙水鸟而言, 它的规划尤为重要。本研究于2016-2018年间在中国、蒙古国和俄罗斯捕捉6只斑头雁(Anser indicus)、5只白琵鹭(Platalea leucorodia)和10只东方白鹳(Ciconia boyciana)进行卫星追踪, 探讨了黄河流域自然保护区对它们栖息地的保护现状。基于4年累积获取的844,592条高频数据, 分析了这21只水鸟在黄河流域活动的时间和利用的土地类型, 并使用核密度法拟合了3种鸟类的家域。结果表明: 3种鸟类均利用黄河流域湿地作为迁徙途中的停歇地, 其中一部分白琵鹭幼鸟利用黄河流域湿地作为度夏地, 一部分东方白鹳利用黄河三角洲湿地作为越冬地; 3种水鸟在黄河流域内的土地利用情况存在差异, 斑头雁对草地(49.0%)、裸地(26.2%)与水体(22.5%)的利用率较高, 白琵鹭对农田(42.1%)、草地(19.8%)和湿地(19.6%)的利用率较高, 东方白鹳对湿地(49.8%)、农田(34.5%)和水体(4.6%)的利用率较高; 斑头雁核心的50%家域被现有保护区完全覆盖, 而白琵鹭和东方白鹳核心的50%家域被现有保护区的覆盖度分别为1.6%和0, 表明后2种水鸟的栖息地极大可能存在保护空缺; 同时对覆盖范围内土地类型自身占比进行分析, 发现3种鸟类对于裸地、草地和农田的利用偏向于被动选择, 而对于湿地和水体的利用表现为主动选择。基于卫星追踪获得的高频数据可以准确反映3种水鸟在黄河流域的停歇情况、土地利用情况及潜在栖息位点。在黄河流域自然保护区的进一步规划中, 应关注白琵鹭和东方白鹳适宜生境的保护状况, 并建立覆盖全面的保护区。     

Peripheral adipose tissue insulin resistance alters lipid composition and function of hippocampal synapses

Compelling evidence indicates that type 2 diabetes mellitus, insulin resistance (IR), and metabolic syndrome are often accompanied by cognitive impairment. However, the mechanistic link between these metabolic abnormalities and CNS dysfunction requires further investigations. Here, we evaluated whether adipose tissue IR and related metabolic alterations resulted in CNS changes by studying synapse lipid composition and function in the adipocyte‐specific ecto‐nucleotide pyrophosphate phosphodiesterase over‐expressing transgenic (AtENPP1‐Tg) mouse, a model characterized by white adipocyte IR, systemic IR, and ectopic fat deposition. When fed a high‐fat diet, AtENPP1‐Tg mice recapitulate essential features of the human metabolic syndrome, making them an ideal model to characterize peripherally induced CNS deficits. Using a combination of gas chromatography and western blot analysis, we found evidence of altered lipid composition, including decreased phospholipids and increased triglycerides (TG) and free fatty acid in hippocampal synaptosomes isolated from high‐fat diet‐fed AtENPP1‐Tg mice. These changes were associated with impaired basal synaptic transmission at the Schaffer collaterals to hippocampal cornu ammonis 1 (CA1) synapses, decreased phosphorylation of the GluN1 glutamate receptor subunit, down‐regulation of insulin receptor expression, and up‐regulation of the free fatty acid receptor 1.

     

Immunohistochemical analysis of substance P containing nerve fibres and their contacts with mast cells in the diabetic rat's tongue

Sensory neuropathy is common symptom of the diabetes mellitus and the prevalence of oral lesions is higher in diabetic patients. The distribution of substance P was studied immunohistochemically in streptozotocin induced diabetic rat's tongue. The morphological association of sensory nerves (substance P immunoreactive) with mast cells (nerve fibre-mast cell contact) was monitored. The substance P nerve fibre mast cell contacts were very scanty in control tongue. The number of substance P nerve terminals and mast cells was significantly increased (p < 0.05) in diabetes mellitus after 4 weeks of the treatment compared with the control tongue. The number of mast cell nerve contacts was even more significantly increased (p < 0.001) in diabetes. The distance between nerve fibres and mast cells was about 1 mm and very often less than 200 nm. In some instances, the mast cells were degranulated in the vicinity to nerve fibres. Increased number of mast cell nerve contacts in neurogenic inflammation might cause vasoconstriction and lesions of the oral mucosa, so some disorders such lichen planus, leukoplakia and cancer might frequently develop in diabetes mellitus.     

Effects of medial collateral ligament release,limb correction,and soft tissue laxity on knee joint contact force distribution after medial opening wedge high tibial osteotomy: a computational study

In this study, the effects of medial collateral ligament (MCL) release and the limb correction strategies with pre-existing MCL laxity on tibiofemoral contact force distribution after high tibial osteotomy (HTO) were investigated. The medial and lateral contact forces of the knee were quantified during simulated standing using computational modeling techniques. MCL slackness had a primary influence on contact force distribution of the knee, while there was little effect of simulated limb correction. Anterior and middle bundle release, which involved the partial release of two-thirds of the superficial MCL, was shown to be an optimal surgical method in HTO, achieving balanced contact distribution in simulated weight-bearing standing.