C1q/肿瘤坏死因子相关蛋白6在肥胖及胰岛素抵抗中的研究进展

C1q/肿瘤坏死因子相关蛋白6(CTRP6)是CTRP超家族中的一员,诸多研究证明,CTRP在胰岛素抵抗及肥胖的形成中起到重要作用,因而研究其参与的作用及具体机制,有助于为胰岛素抵抗及肥胖的治疗指明方向。文章主要对CTRP6的结构、分布及其促进胰岛素抵抗与肥胖的相关生理功能的研究进展进行综述。     

CTRP家族在代谢相关性疾病中的作用

补体C1q/肿瘤坏死因子相关蛋白(complement-C1q/tumor necrosis factor-related protein,CTRP)家族是一类主要由脂肪组织分泌的脂肪因子超家族,结构特征相似,具有抗炎、胰岛素增敏、调节代谢和免疫等生物学功能。目前已经发现的CTRP家族成员包括CTRP1~15。研究发现CTRP家族与代谢相关疾病如糖尿病、肥胖、冠心病等密切相关。     

与胰岛素抵抗有关的脂肪分泌蛋白：血清视黄醇结合蛋白4

在人类和啮齿类动物胰岛素抵抗状态下,葡萄糖转运子4（GLUT4）的表达在脂肪细胞中选择性减少,而脂肪组织特异性GLUT4基因敲除小鼠可产生继发性的肌肉及肝脏的胰岛素抵抗,提示脂肪组织可分泌一种循环因子,导致全身性胰岛素抵抗.研究发现,血清视黄醇结合蛋白4（RBP4）可能与此相关.     

脂肪组织炎症与肥胖关系的研究进展

脂肪组织是一个重要的内分泌器官,可分泌瘦素、单核细胞趋化蛋白-1（MCP-1）和脂联素等大量脂肪因子,这些因子与许多生理和病理过程有关.有研究显示,脂肪组织中的脂质代谢与激素和交感神经系统密切相关.如在禁食状态下儿茶酚胺诱导脂肪分解以提供脂肪酸,而在进食状态下胰岛素抑制脂肪分解并促进脂肪合成.当脂肪组织不能满足储存过多能量的时候,甘油三酯会在非脂肪组织储存导致异位脂肪形成,进而导致肝脏和骨骼肌胰岛素抵抗及胰腺的胰岛素分泌减少.研究表明,肥胖是一种与慢性、低度炎症相关的状态,并可导致胰岛素抵抗.腹型肥胖中具有抗炎和促炎作用的脂肪因子生成不平衡是导致多种代谢综合征的重要原因,脂肪组织在巨噬细胞浸润之前或同时均伴有胰岛素抵抗和异位脂肪沉积,说明巨噬细胞浸润对肥胖的发生有重要意义.为此,本文结合文献,就脂肪组织炎症与肥胖的关系作一综述.     

衰老相关的慢性炎症与胰岛素抵抗的研究进展

慢性炎症是衰老和衰老相关疾病的一个主要发病风险因素,而胰岛素抵抗也在衰老过程中发挥作用。慢性炎症通过损害正常的脂质分布、脂肪组织功能、线粒体功能以及内质网应激引起胰岛素抵抗。脂肪组织的异常分布又可引起慢性炎症,慢性炎症进一步加剧胰岛素抵抗,慢性炎症和胰岛素抵抗相互作用可加速衰老过程。然而,一些研究表明,胰岛素抵抗本身也增加慢性炎症的作用。其中胰岛素依赖Akt信号传导通路的活性特别重要,因为它在胰岛素敏感器官如肝脏和肌肉中分布减少,并在非代谢器官如肾和主动脉中分布增加,原因可能是胰岛素抵抗和高胰岛素血症。     

补体C1q／肿瘤坏死因子相关蛋白3对3T3-L1脂肪细胞脂肪因子表达的影响

目的：观察脂肪因子补体C1q/肿瘤坏死因子（TNF）相关蛋白3（CTRP3）对3T3-L1脂肪细胞脂联素（APN）、瘦素（LPT）、内脏脂肪素（VFT）及爱帕琳肽（APL）等脂肪因子表达的调节效应,以及胰岛素抵抗对该调节效应的影响。方法以软脂酸诱导胰岛素抵抗的3 T3-L1脂肪细胞模型,分别以10、50、250μg/L CTRP3干预正常3T3-L1脂肪细胞12以及250μg/L CTRP3干预胰岛素抵抗的3T3-L1脂肪细胞12 h。分别通过酶联免疫吸附法（ ELISA）及实时定量-聚合酶链反应（ RT-PCR）法检测脂肪因子蛋白分泌量及基因表达水平。组间差异采用方差分析,两组间进一步比较采用SNK-q检验。结果250μg/L CTRP3干预正常组APN、LPT、VFT及APL蛋白分泌量较正常对照组分别增加了63.3％、42.9％、57.1％及56.0％（ q＝8.605、8.526、8.284、8.573,均 P＜0.05）;10及50μg/L干预组上述脂肪因子蛋白分泌量呈增加趋势,但除50μg/L CTRP3干预组APL蛋白分泌量较对照组显著增加外[（6.2＆#177;1.1）比（5.0＆#177;0.9）μg/L, q＝4.593,P＜0.05],其余均差异无统计学意义（均P＞0.05）;其基因表达变化趋势与此类似,并且在干预浓度为50μg/L时APN、LPT、VFT及APL mRNA表达水平较正常对照组分别增加22.0％、13.0％、20.0％及33.0％（ q＝6.150、3.987、5.653、9.031,均P＜0.05）。与CTRP3（250μg/L）干预正常脂肪细胞相比,CTRP3（250μg/L）干预胰岛素抵抗脂肪细胞APN、LPT、VFT及APL蛋白分泌量分别降低了28.6％、21.0％、24.5％及17.9％（ q＝6.341、5.969、5.592、4.287,均 P ＜0.05）,基因表达降低了21.6％、17.2％、15.6％及18.9％（q ＝9.225、7.668、7.066、8.210,均P＜0.05）。结论 CTRP3浓度依赖性地增加3T3-L1脂肪细胞APN、LPT、VFT及APL的表达,胰岛素抵抗降低该调节效应。     

辛伐他汀对胰岛素抵抗大鼠脂肪组织脂联素和核因子κB抑制因子激酶mRNA表达的影响

目的探讨辛伐他汀对胰岛素抵抗大鼠脂肪组织脂联素和核因子κB抑制因子激酶mRNA表达的影响。方法采用高脂饲料喂养复制胰岛素抵抗大鼠模型,并用正常血糖—高血浆胰岛素钳夹技术评估。胰岛素抵抗大鼠给予辛伐他汀10mg/(kg.d)治疗。应用逆转录聚合酶链反应检测大鼠脂肪组织中脂联素和核因子κB抑制因子激酶mRNA的表达。结果高脂饲料喂养组大鼠葡萄糖输注率明显低于基础饲料喂养组[0.76±0.28mg/(kg.min)比4.26±0.70mg/(kg.min),P<0.01]。辛伐他汀治疗组和高脂未治疗组大鼠脂肪组织中脂联素mRNA的表达差异无显著性(0.25±0.12比0.29±0.11,P>0.05),但均明显低于基础饲料喂养组(1.18±0.12,P<0.05)。辛伐他汀治疗组大鼠脂肪组织中核因子κB抑制因子激酶mRNA的表达明显低于高脂未治疗组(0.15±0.03比1.21±0.03,P<0.05),与基础饲料喂养组差异无显著性(0.15±0.03,P>0.05)。除外辛伐他汀干预作用后大鼠脂肪组织脂联素与核因子κB抑制因子激酶mRNA的表达负相关(r=-0.97,P=0.000)。结论辛伐他汀不能增加高脂诱导的胰岛素抵抗大鼠脂肪组织脂联素mRNA的表达,但能使升高的核因子κB抑制因子激酶mRNA表达水平得以恢复,这可能得益于辛伐他汀调脂作用外的抗炎作用。     

脂肪固有免疫细胞与胰岛素抵抗

胰岛素抵抗是指外周组织对胰岛素敏感性及反应性降低,肥胖是胰岛素抵抗的主要原因.近年来研究显示,脂肪组织内的炎性反应状态与胰岛素抵抗及2型糖尿病等代谢疾病之间存在密切关系,而脂肪组织中的巨噬细胞、肥大细胞、中性粒细胞、树突状细胞、嗜酸性粒细胞以及自然杀伤T细胞等多种固有免疫细胞通过活化和释放炎性反应介质,参与炎性反应,从而促进机体胰岛素抵抗的形成.进一步深入阐明固有免疫细胞在脂肪组织炎性反应和胰岛素抵抗方面的作用,可以为糖尿病基础研究和治疗提供新的方向和思路.     

脂肪组织巨噬细胞浸润与胰岛素抵抗

肥胖是一种低度炎性反应状态.近年来发现肥胖个体脂肪组织中巨噬细胞的浸润显著增加,并有研究表明脂肪组织的炎性反应因子主要由浸润的巨噬细胞分泌.目前对脂肪组织巨噬细胞的来源以及影响其浸润的因素还有争论.研究发现,巨噬细胞可以通过抑制脂肪细胞分化,增加炎性反应因子的表达等导致胰岛素抵抗的发生、发展.     

Adiponectin--一种新的脂肪细胞因子

脂肪组织能分泌一系列脂肪细胞因子(adipocytokines)参与机体的能量代谢，并与肥胖、胰岛素抵抗及其并发症密切相关。新近又发现一种脂肪细胞因子，即脂联素(adi—ponectin)，它是脂肪组织特异性分泌的具有类似胶原结构的蛋白，在肥胖、胰岛素抵抗、2型糖尿病及动脉粥样硬化的患者其浓度明显低于正常人，被认为是胰岛素抵抗和糖尿病大血管病变的保护因子。     

Age-associated loss in adiponectin-activation by caloric restriction: lack of compensation by enhanced inducibility of adiponectin paralogs CTRP2 and CTRP7

Hormonal signals from adipose tissue regulate energy homeostasis but may also be involved in the anti-aging effects of caloric restriction. The purpose of the current study was the investigation of age-dependent effects of caloric restriction on the release of adiponectin, on the expression and activation of adiponectin-related signaling and on parameters of altered insulin sensitivity. In young and in senescent rats, 2 months moderate caloric restriction reduces serum leptin and insulin (young: -50%; old: -30%) suggesting increased insulin sensitivity. However, the same diet enhances serum adiponectin in young (+60%) but not in senescent (+2%, n=NS) rats. Similarly, adiponectin expression (visceral fat) and muscular AdipoR1/2 expression are induced in young rats but not in senescent rats. The locally produced adiponectin paralogs CTRP2/7 are elevated in muscular tissues of old animals (CTRP2 protein: +40%; CTRP7 protein: +50%) and further induced by caloric restriction but this does not result in an increased activation of their downstream target AMPK. Thus, aging is associated with a partial loss of adiponectin inducibility following moderate caloric restriction. This loss is not sufficiently compensated by the locally induced adiponectin paralogs CTRP2/7, although caloric restriction results in increased insulin sensitivity in young and in senescent animals. Thus, the improvement in insulin sensitivity appears to be independent of adiponectin induction by caloric restriction in this model.     

Complement c1q tumor necrosis factor-related protein 3 a novel adipokine,protect against diabetes mellitus in young adult Egyptians

C1q/TNF-related protein-3 (CTRP3) is a novel adipokine with anti-inflammatory and a multitude of biological effects on glucose and lipid metabolism however, the influence of CTRP3 on incidence of diabetes mellitus remain unclear. This study investigated the effects of CTRP3 levels in obese and normal body weight young adults on insulin resistance and occurrence of diabetes mellitus.Subjects and methodsIn this case control study, Serum levels of CTRP3, HbA1c, Lipid profile, glucose and insulin levels were determined in 75 obese and 68 normal body weight individuals.ResultsIn obese young adults CTRP3 concentrations were decreased compared to normal body weight young adults (NBW). The association between reduction of CTRP3 concentrations and the presence of diabetes is statistically significant. CTRP3 showed significant negative correlation with BMI, HOMA-IR and triglycerides as well as positive correlations with HDL – cholesterol while there is no association between CTRP3 and BMI within the NBW group. Higher HbA1C, HOMA-IR, and risk of diabetes development within obese subjects were related to lower CTRP3 concentration.ConclusionsThis study shows that reduction of CTRP3 concentrations is likely to bring a concomitant increase in risk of diabetes in obese and normal body weight young adults. Decrease in CTRP3 concentration may have an essential role in the pathophysiology of metabolic disorders concomitant to obesity.     

The gene expression of CTRP12 but not CTRP13 is upregulated in both visceral and subcutaneous adipose tissue of obese subjects

Obesity is a well-known chronic low-grade inflammation condition characterized by dysregulated adipokine secretion and function. Both CTRP12 and CTRP13 are adipokines that influence glucose and lipid metabolism. We aimed to investigate CTRP12, CTRP13, and inflammatory gene expressions in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from obese women who underwent bariatric surgery in comparison with the normal weight women. This case-control study included 20 obese [body mass index (BMI) > 35–40 kg/m²] candidates for bariatric surgery and 20 normal-weight women (BMI <25 kg/m²) as control group, who underwent elective surgeries. Real-time PCR was used to evaluate mRNA expression levels of CTRP12, CTRP13, and inflammatory genes in SAT and VAT from both groups. We observed significantly higher mRNA expression of CTRP12 in SAT (p = 0.048) and VAT (p = 0.046) from obese patients compared to the controls. There was significantly greater expression of IL-6 and MCP-1 inflammatory genes in SAT (p = 0.013 and p = 0.005 respectively) and VAT (p = 0.000 and p = 0.001 respectively) of obese patients compared to the control group. IL-1β (p = 0.015) and TNF-α (p = 0.014) expressions significantly increased in VAT from obese patients compared to the control group. Spearman correlation analysis showed that CTRP12 expression significantly correlated with obesity indices. Our findings showed that CTRP12 significantly increased in both VAT and SAT of obese group. More importantly, we observed a positive correlation between CTRP12 with inflammatory parameters. These results indicated that CTRP12 might be part of an intricate network for glucose metabolism and obesity-related inflammation processes.     

Fat depot-specific expression of adiponectin is impaired in Zucker fatty rats

Adiposity, particularly increased intra-abdominal fat, is a predisposing factor for the development of insulin resistance in obesity and type 2 diabetes. Visceral fat seems to differ from subcutaneous adipose tissue in adipocytokine production. This fat depot-related difference has been viewed as an important mechanism by which adipose tissue exerts its paracrine/autocrine effects on peripheral tissue in modulating insulin sensitivity. We have studied the relative expression of adiponectin in visceral versus subcutaneous fat in Zucker fatty versus lean rats. Visceral fat, as opposed to subcutaneous fat, exhibited relatively higher levels of adiponectin production in lean animals. However, in Zucker fatty rats, adiponectin expression in visceral fat was suppressed to basal levels, which correlated with significantly reduced plasma adiponectin concentrations and increased insulin resistance. These results suggest that an impaired depot-specific expression of adiponectin is a contributing factor for the development of insulin resistance in Zucker fatty rats.     

Metabolic function of the CTRP family of hormones

Maintaining proper energy balance in mammals entails intimate crosstalk between various tissues and organs. These inter-organ communications are mediated, to a great extent, by secreted hormones that circulate in blood. Regulation of the complex metabolic networks by secreted hormones (e.g., insulin, glucagon, leptin, adiponectin, FGF21) constitutes an important mechanism governing the integrated control of whole-body metabolism. Disruption of hormone-mediated metabolic circuits frequently results in dysregulated energy metabolism and pathology. As part of an effort to identify novel metabolic hormones, we recently characterized a highly conserved family of 15 secreted proteins, the C1q/TNF-related proteins (CTRP1-15). While related to adiponectin in sequence and structural organization, each CTRP has its own unique tissue expression profile and non-redundant function in regulating sugar and/or fat metabolism. Here, we summarize the current understanding of the physiological functions of CTRPs, emphasizing their metabolic roles. Future studies using gain-of-function and loss-of-function mouse models will provide greater mechanistic insights into the critical role CTRPs play in regulating systemic energy homeostasis.     

C1q/TNF-related protein-3 and glucose homeostasis

Adipokines are cytokines produced by adipocytes that may mediate inflammatory processes, whilst adipocyte-derived proteins may have the converse effect. C1q/TNF-related protein-3 or CTRP3 is a novel adipokine that is expressed and released by most types of human tissues including adipose tissue. This adipokine, considered as an adiponectin, can normalize blood glucose by several mechanisms. In addition, it can modulate the expression/secretion of other cytokine and adipokines leading to lower insulin resistance in peripheral tissues. Beneficial effects of CTRP3 against hyperglycemia-induced complications in the kidney and eye have been reported. In this review, we have presented the latest findings on the in vitro and in vivo hypoglycemic effects of CTRP3, followed by the findings on the preventive/therapeutic effects of CTRP3 adipokines against diabetes related complications.     

Changes in abdominal subcutaneous fat water content with rapid weight loss and long-term weight maintenance in abdominally obese men and women

OBJECTIVE: Insulin resistance decreases blood flow and volume in fat tissue. We hypothesised that fat tissue nutritive blood flow and volume, and thereby water content, would increase during weight loss and weight maintenance in obese persons. DESIGN: Longitudinal clinical intervention with a 9-week very-low-calorie diet (VLCD) followed by one year of weight maintenance. SUBJECTS: Obese men (n=13) and women (n=14) with the metabolic syndrome. MEASUREMENTS: Water content of abdominal subcutaneous fat tissue as estimated by a sensor on the skin surface measuring the dielectric constant at 300 MHz. Anthropometric measures of fatness and fat distribution. Biochemical measures related to insulin resistance. RESULTS: Subjects lost 14.5+/-3.4% of body weight during the VLCD, and generally sustained this weight loss during weight maintenance. Insulin sensitivity as estimated by an index (qualitative insulin sensitivity check index) increased during the VLCD, and remained increased throughout weight maintenance. The dielectric constant increased from 23.3+/-2.3 to 25.0+/-2.1 (P<0.001) during the VLCD, and further to 27.8+/-1.9 (P<0.001) during weight maintenance, indicating an increase in the water content of subcutaneous fat. The increase in subcutaneous fat water content did not correlate with weight loss and other measures of adiposity during the VLCD, but there was an inverse correlation that strengthened in significance from baseline to 6, 9 and 12 mo (r=-0.32 to -0.64, P=0.079-0.002). Increases in subcutaneous fat water content also correlated with improvements in insulin sensitivity at 6, 9 and 12 months of weight maintenance (r=0.34-0.54, P=0.094-0.006). CONCLUSIONS: Water content of abdominal subcutaneous adipose tissue increases with weight loss in obese persons with the metabolic syndrome, and may reflect increased subcutaneous fat tissue nutritive blood flow. The increase in water content correlates with the increase in insulin sensitivity, suggesting that weight loss and consequent improved insulin sensitivity could mediate the increase in abdominal subcutaneous fat hydration.