半乳糖苷凝集素Galectin3直接诱发胰岛素抵抗

肥胖时,巨噬细胞和其他免疫细胞在胰岛素靶组织大量聚集,分泌一系列促炎症细胞因子[包括TNFα(tumor necrosis factorα)和IL1β(interleukine 1β)],导致慢性炎症状态。研究表明,由CD11c阳性巨噬细胞引起慢性炎症诱发胰岛素抵抗。然而,通过抑制TNFα或IL1β等方法来改善胰岛素抵抗的临床研究并不成功。该课题组之前的研究发现,将肥胖小鼠由高脂饮食更换到正常饮食后,脂肪组织中CD11c阳性巨噬细胞所表达的半乳糖苷凝集素3(Galectin3,Gal3)水平大幅降低。同时,在这些更换饮食的小鼠中,尽管脂肪组织CD11c阳性巨噬细胞数目相比高脂饮食喂养时并没有变化,但炎症和胰岛素抵抗却得到了明显改善。因此,该课题组提出,Gal3是介导炎症致胰岛素抵抗的关键分子。Gal3是一种主要由巨噬细胞分泌的凝集素,其水平在肥胖病人和肥胖小鼠中都显著增加。在胰岛素敏感性正常小鼠上,给予Gal3可导致胰岛素抵抗和葡萄糖不耐受,通过基因敲除或药物抑制Gal3则可在肥胖小鼠上改善胰岛素抵抗。体外实验表明,Gal3可直接增加巨噬细胞的化学趋化性,减少肌肉细胞和3T3-L1脂肪细胞中胰岛素刺激的葡萄糖摄取,并可在原代肝细胞中阻碍胰岛素对肝糖输出的抑制作用。更重要的是,该课题组发现,Gal3可与胰岛素受体结合并抑制其下游信号传导。这些发现阐明了Gal3在胰岛素三大作用靶细胞中的新作用,Gal3为连接炎症和胰岛素敏感性减低的关键分子,抑制Gal3有望成为胰岛素抵抗和糖尿病的新治疗手段。     

脂肪细胞与免疫细胞在脂肪组织炎症与代谢失调中的作用

肥胖和超重的患病率继续上升,发病率和死亡率日益增长,是造成高血压、高脂血症、动脉粥样硬化、2型糖尿病等疾病的关键因素之一。目前,针对肥胖的研究已经深入到分子层面。结果提示,肥胖状态下内脏脂肪组织中的低度、慢性炎症反应被认为是其导致胰岛素抵抗的重要病理生理机制。这篇评论的目的是总结目前先天性免疫细胞和适应性免疫细胞在脂肪组织炎症和免疫细胞失调在肥胖和胰岛素抵抗中的作用,认识免疫炎症与代谢之间关系可能为临床治疗肥胖提供靶向。     

肥胖与慢性炎症

肥胖及其相关的代谢类疾病严重影响人类的健康,而肥胖诱导的慢性炎症是胰岛素抵抗和代谢综合症发病的关键因素.脂肪组织慢性炎症发生的机制及其与代谢综合症的关系已经成为全球瞩目的研究热点.慢性炎症的特征主要包括脂肪组织中促炎细胞因子表达量增加,抗炎细胞因子表达量降低以及大量巨噬细胞浸润.鉴于肥胖及其相关代谢综合症对人类健康的巨大危害,现对慢性炎症的发生机制,肥胖和慢性炎症之间的关系,脂肪组织炎症中巨噬细胞浸润以及和信号传导通路进行综述.     

脂肪组织氧化应激与运动干预

脂肪组织在调控代谢稳态和运动适应中扮演着重要的角色。肥胖引起的脂肪组织氧化应激是2型糖尿病与代谢综合征等的重要病理特征,是促进脂肪组织炎症和胰岛素抵抗的重要机制。氧化应激可以引起脂肪细胞趋化因子表达,募集炎症细胞浸润脂肪组织,炎症细胞分泌大量的炎症因子,并促进了局部和系统的胰岛素抵抗与慢性炎症。运动对肥胖相关的慢性代谢病的有效干预与运动的抗氧化效应相关。本文总结了氧化应激在脂肪组织炎症和胰岛素抵抗中的作用,以及运动对脂肪组织氧化应激的调控。     

抵抗素基因表达的调控因素

抵抗素是一种主要由脂肪组织分泌的多肽类激素。它与肥胖、2型糖尿病、胰岛素抵抗等疾病具有相关性,并受多种因素调控。胰岛素和抗糖尿病药物、激素、细胞因子、神经递质、营养与饮食等都参与抵抗素基因表达的调控。对抵抗素的深入研究将有助于了解胰岛素抵抗相关疾病的发病机制,为糖尿病、肥胖等的防治提供实验基础。     

瘦素受体的研究进展

瘦素的体重调节作用是通过瘦素受体介导的。随着分子生物学技术的发展,已以受体的基因表达、结构、功能等方面取得了一些进展。肥胖患者常合并高胰岛素血症、胰岛素抵抗和瘦素抵抗,说明瘦素受体与肥胖及其相关疾病有着不可分割的联系。     

运动改善肥胖症瘦素抵抗及其机制研究进展

大部分肥胖患者体内出现瘦素抵抗,表现为血清瘦素水平异常升高,但机体对瘦素不敏感或无反应,使瘦素抑制食欲、增加能量消耗和降低血糖等功能不能有效发挥.减轻瘦素抵抗被认为是治疗肥胖及肥胖相关疾病的有效途径.运动减轻肥胖、改善糖脂代谢和增强胰岛素敏感性的作用与运动降低瘦素水平、改善瘦素抵抗密切相关.本文在概述瘦素实现生理功能的机制、肥胖症的中枢及外周瘦素抵抗的基础上,主要综述近年来运动减轻肥胖症瘦素抵抗机制的研究进展,包括减轻高瘦素血症、改善中枢和外周瘦素抵抗,以期为运动防治肥胖机制的研究提供新视角.     

胰岛素信号通路、炎症信号通路与泛素-蛋白酶体系统的交互作用

胰岛素抵抗是肥胖和2型糖尿病的主要表征。胰岛素信号通路根据是否需要胰岛素受体底物(insulin receptor substrate,IRS)介导可分为IRS介导和非IRS介导的信号通路,其中以IRS介导的信号通路为主。肥胖可增强炎性细胞因子表达并活化IKKβ/NF-κB和JNK等炎症信号通路,抑制IRS酪氨酸磷酸化,从而阻止胰岛素的信号转导,降低胰岛素的敏感性,表现为胰岛素抵抗。泛素-蛋白酶体系统作为机体蛋白降解的主要途径,与胰岛素和炎症信号通路联系密切,一方面胰岛素信号通路的阻断可活化泛素依赖的蛋白降解,另一方面,泛素依赖的蛋白降解系统也可直接降解胰岛素和炎症信号通路的关键蛋白,影响胰岛素的作用。本文拟综述肥胖时,胰岛素信号通路、炎症相关信号通路和泛素-蛋白酶体系统之间的交互作用,在分子水平上探讨胰岛素抵抗的发生机制。     

肠道菌群影响宿主肥胖的研究进展

越来越多的研究结果表明,肠道菌群与宿主消化、呼吸、内分泌、心血管、神经等系统发生的疾病密切相关。目前,全世界患肥胖和Ⅱ型糖尿病的人逐渐增多。肠道菌群的平衡有利于维持宿主正常的能量代谢过程,而肠道菌群失调使机体产生慢性炎症反应及胰岛素抵抗,从而导致肥胖和Ⅱ型糖尿病等代谢性疾病的发生。本文综述了肠道菌群影响肥胖的机制,以及通过调控肠道菌群改善肥胖的方法。     

糖皮质激素与脂肪代谢和胰岛素抵抗

内源性和外源性糖皮质激素过多会导致胰岛素抵抗和发展为糖尿病.糖皮质激素增加循环中葡萄糖、胰岛素和游离脂肪酸(FFA)浓度.循环中FFA增高与肥胖、胰岛素抵抗和2型糖尿病密切相关,其主要来源于脂肪细胞内甘油三酯水解.糖皮质激素刺激脂肪分解、增加FFA构成了激素导致胰岛素抵抗的重要机制之一.     

Insulin resistance,selfish brain,and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases

Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others).     

Adipose tissue inflammation in diabetes and heart failure

Adipose tissue inflammation induces systemic insulin resistance in persons with obesity and heart failure, and has a crucial role in the progression of these diseases. Chronic inflammatory processes share a common mechanism in which increased production of reactive oxygen species activates p53 and NF-κB signaling, leading to up-regulation of pro-inflammatory cytokine expression and impairment of glucose metabolism. Since inhibition of these processes could slow the progression of various diseases, targeting adipose inflammation has the potential to become a new therapeutic approach for diabetes and heart failure.     

Toll-like receptors, inflammation, metabolism and obesity

Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance.     

Relationships Among Obesity,Inflammation, and Insulin Resistance in African Americans and West Africans

Several research studies in different populations indicate that inflammation may be the link between obesity and insulin resistance (IR). However, this relationship has not been adequately explored among African Americans, an ethnic group with disproportionately high rates of obesity and IR. In this study, we conducted a comparative study of the relationship among adiposity, inflammation, and IR in African Americans and West Africans, the ancestral source population for African Americans. The associations between obesity markers (BMI and waist‐to‐hip ratio (WHR)), inflammatory markers (high‐sensitivity C‐reactive protein (hsCRP), haptoglobin, interleukin (IL)‐6, and tumor necrosis factor (TNF)‐α), and IR (homeostasis model assessment of insulin resistance (HOMA_IR)) were evaluated in 247 West Africans and 315 African Americans. In average, African Americans were heavier than the West Africans (by an average of 1.6 BMI units for women and 3 BMI units for men). Plasma hsCRP, haptoglobin, and IL‐6 (but not TNF‐α level) were higher in African Americans than in West Africans. In both populations, BMI was associated with markers of inflammation and with HOMA_IR, and these associations remained significant after adjusting for sex and age. However, the pattern of associations between measured inflammatory markers and IR was different between the two groups. In West Africans, hsCRP was the only inflammatory marker associated with IR. In contrast, hsCRP, haptoglobin, and IL‐6 were all associated with IR in African Americans. Interestingly, none of the associations between markers of inflammation and IR remained significant after adjusting for BMI. This finding suggests that in African Americans, the relationship between inflammatory markers and IR is mediated by adiposity.     

Impact of obesity on IL-12 family gene expression in insulin responsive tissues

Mounting evidence has established a role for chronic inflammation in the development of obesity-induced insulin resistance, as genetic ablation of pro-inflammatory cytokines and chemokines elevated in obesity improves insulin signaling in vitro and in vivo. Recent evidence further highlights interleukin (IL)-12 family cytokines as prospective inflammatory mediators linking obesity to insulin resistance. In this study, we present empirical evidence demonstrating that IL-12 family related genes are expressed and regulated in insulin-responsive tissues under conditions of obesity. First, we report that respective mRNAs for each of the known members of this cytokine family are expressed within detectable ranges in WAT, skeletal muscle, liver and heart. Second, we show that these cytokines and their cognate receptors are divergently regulated with genetic obesity in a tissue-specific manner. Third, we demonstrate that select IL-12 family cytokines are regulated in WAT in a manner that is dependent on the developmental stage of obesity as well as the inflammatory progression associated with obesity. Fourth, we report that respective mRNAs for IL-12 cytokines and receptors are also expressed and divergently regulated in cultured adipocytes under conditions of inflammatory stress. To our knowledge, this report is the first study to systemically evaluated mRNA expression of all IL-12 family cytokines and receptors in any tissue under conditions of obesity highlighting select family members as potential mediators linking excess nutrient intake to metabolic diseases such as insulin resistance, diabetes and heart disease.     

Immunity as a link between obesity and insulin resistance

Obesity is a major public health problem in the United States and worldwide. Further, obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and type-2 diabetes (T2D). A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesity-induced insulin resistance. This adipose tissue inflammation is characterized by changes in immune cell populations giving rise to altered adipo/cytokine profiles, which in turn induces skeletal muscle and hepatic insulin resistance. Detailed molecular mechanisms of insulin resistance, adipose tissue inflammation and the implications of these findings on therapeutic strategies are discussed in this review.     

Inflammation and insulin resistance

Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state.