骨桥蛋白和肥胖

骨桥蛋白(OPN)是细胞外基质中一种重要的功能性蛋白和前炎性反应细胞因子.研究表明,OPN在肥胖者体内脂肪组织中的表达明显上调,且主要由脂肪组织巨噬细胞所分泌.它可通过介导巨噬细胞的趋化和增强单核细胞趋化蛋白(MCP)-1的作用来促进巨噬细胞在脂肪组织中的蓄积,还可引起肥胖相关的脂肪组织炎性反应因子的增加,在肥胖、胰岛素抵抗的发生过程中起重要作用.     

骨桥蛋白和肥胖

骨桥蛋白（OPN）是细胞外基质中一种重要的功能性蛋白和前炎性反应细胞因子.研究表明,OPN在肥胖者体内脂肪组织中的表达明显上调,且主要由脂肪组织巨噬细胞所分泌.它可通过介导巨噬细胞的趋化和增强单核细胞趋化蛋白（MCP）-1的作用来促进巨噬细胞在脂肪组织中的蓄积,还可引起肥胖相关的脂肪组织炎性反应因子的增加,在肥胖、胰岛素抵抗的发生过程中起重要作用.     

microRNA与脂肪组织慢性低度炎性反应

脂肪组织慢性低度炎性反应是肥胖、2型糖尿病、高血压、心血管疾病等代谢性疾病的中心环节.研究脂肪组织慢性低度炎性反应的精确调控过程,对于预防和治疗肥胖及相关疾病有重要意义.microRNA是一类非编码RNA,具有调节基因表达的功能.研究显示,microRNA对脂肪组织巨噬细胞、经典炎性反应信号通路及炎性因子、抗炎因子等具有调控作用.     

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.     

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.     

核因子-κB与肥胖

核因子-κB(NF-κB)是独特的核转录因子,广泛存在于高级真核生物的各种细胞中,参与炎性反应、分化和凋亡等多种细胞反应.近年来的研究显示,NF-κB在肥胖的发病中起重要作用.NF-κB可能通过促进脂肪组织炎性反应、抑制脂肪细胞分化以及调节脂肪细胞凋亡而参与肥胖的发生与发展.     

IKKε调节代谢平衡及其机制

炎性反应是连接肥胖和胰岛素抵抗的重要桥梁.肥胖相关的慢性低度炎性反应严重影响了胰岛素的敏感性.高脂饮食会激活炎性通路核因子-κB,从而导致该通路中的非经典激酶核因子-κB抑制蛋白激酶ε(IKKe)在肝脏和脂肪组织中持续激活.近期研究证明,IKKε在代谢平衡中扮演重要角色,通过基因敲除或药物抑制该激酶的表达能通过各种不同机制影响脂肪组织内热量的消耗,从而减轻体重,改善糖、脂代谢.这些研究提示:IKKε是一种与代谢平衡密切相关的炎性激酶,可能成为肥胖及代谢性疾病治疗的新靶点.     

炎性反应——肥胖和胰岛素抵抗的重要特征

肥胖和胰岛素抵抗呈现一种慢性炎性反应状态,表现为白细胞介素-6、白细胞介素-1β、巨噬细胞趋化因子等炎性反应因子水平升高.其原因在于能量代谢不平衡导致脂肪细胞肥大、增生、内质网应激和线粒体功能障碍,c-Jun氨基末端激酶(JNK)/激活蛋白(AP)-1和核因子(NF)-KB抑制蛋白激酶(IKK)β/NF-κKB两条信号通路活化,脂肪因子、游离脂肪酸和其他炎性反应介质表达增高,进而影响了全身各器官如肝脏、胰岛β细胞和骨骼肌.单核细胞和巨噬细胞是炎性反应因子另一个重要的来源.肥胖导致的JNK活化通过胰岛素受体底物-1的丝氨酸磷酸化影响胰岛素信号转导.饮食、运动、降低体重和药物可以改变炎性反应因子的水平.炎性反应理论为代谢性疾病的临床干预提供了重要的方向.     

网膜素与代谢综合征

网膜素是由内脏脂肪组织产生的一种脂肪因子,具有抗炎、增加胰岛素敏感性、抗糖尿病、抗动脉粥样硬化和抗心血管疾病的作用.在肥胖、胰岛素抵抗、炎性反应状态下它的表达明显降低.网膜素与肥胖、糖尿病、心血管疾病的发生密切相关.网膜素的这些作用使其成为治疗这些疾病的一个新靶点.     

脂肪组织在脂肪性肝病发生发展中的作用

肥胖和饮酒容易导致脂肪性肝病,两者均可引起脂肪组织发生改变,主要的改变包括脂肪组织炎性反应、胰岛素抵抗、瘦素等细胞因子异常分泌以及免疫细胞浸润等。脂肪组织和肝脏通过多种途径相互作用,共同参与脂肪性肝病的发生、发展。减肥或使用药物减轻脂肪组织炎性反应均可改善肝脏损伤,提示针对脂肪组织的干预对治疗脂肪性肝病有着重要的作用。该文对脂肪组织在脂肪性肝病发生、发展中的作用作一综述。     

Macrophage recruitment in obese adipose tissue

Obesity is characterized as a chronic state of low‐grade inflammation with progressive immune cell infiltration into adipose tissues. Adipose tissue macrophages play critical roles in the establishment of the chronic inflammatory state and metabolic dysfunctions. The novel discovery that pro‐inflammatory macrophages are recruited to obese adipose tissue prompted an increased interest in the interplay between immune cells and metabolism. Since this discovery, many works have been published investigating the factors that lead to macrophage recruitment, the phenotypic change of adipose tissue macrophages, and metabolic dysfunctions. Adipokines and chemokines are key mediators that play crucial roles in crosstalk between adipocytes and macrophages and in regulating the adipose tissue inflammation. In the present review, we discuss the obesity‐mediated adipose tissue remodelling, and particularly, the role of adipokines/chemokines in macrophage recruitment to obese adipose tissue. This review provides new insights into the physiological role of these factors and identifies a potential therapeutic target for obesity and associated disorders.     

Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue

Infiltration of inflammatory macrophages into adipose tissues with the progression of obesity triggers insulin resistance and obesity-related metabolic diseases. We recently reported that macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood in line with obesity progression and is incorporated into adipocytes, thereby inducing lipolysis in adipose tissue. Here we show that such a response is required for the recruitment of adipose tissue macrophages. In vitro, AIM-dependent lipolysis induced an efflux of palmitic and stearic acids from 3T3-L1 adipocytes, thereby stimulating chemokine production in adipocytes via activation of toll-like receptor 4 (TLR4). In vivo administration of recombinant AIM to TLR4-deficient (TLR4(-/-)) mice resulted in induction of lipolysis without chemokine production in adipose tissues. Consistently, mRNA levels for the chemokines that affect macrophages were far lower in AIM-deficient (AIM(-/-)) than in wild-type (AIM(+/+)) obese adipose tissue. This reduction in chemokine production resulted in a marked prevention of inflammatory macrophage infiltration into adipose tissue in obese AIM(-/-) mice, although these mice showed more advanced obesity than AIM(+/+) mice on a high-fat diet. Diminished macrophage infiltration resulted in decreased inflammation locally and systemically in obese AIM(-/-) mice, thereby protecting them from insulin resistance and glucose intolerance. These results indicate that the increase in blood AIM is a critical event for the initiation of macrophage recruitment into adipose tissue, which is followed by insulin resistance. Thus, AIM suppression might be therapeutically applicable for the prevention of obesity-related metabolic disorders.     

Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes

Obesity is considered a chronic low-grade inflammatory state. The white adipose tissue produces a variety of inflammation-related proteins whose expression is increased in obese subjects. The nonadipose cell fraction, which includes infiltrated macrophages, is a determinant source of inflammation-related molecules within the adipose tissue. Our working hypothesis is that macrophage infiltration affects fat expansion through a paracrine action on adipocyte differentiation. Human primary preadipocytes were then differentiated in the presence of conditioned media obtained from macrophages differentiated from blood monocytes. Preadipocytes treated by macrophage-conditioned medium displayed marked reduction of adipogenesis as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic and lipogenic markers. In addition to this effect, the activation of macrophages by lipopolysaccharides stimulated nuclear factor kappaB signaling, increased gene expression and release of proinflammatory cytokines and chemokines, and induced preadipocyte proliferation. This phenomenon was associated with increased cyclin D1 gene expression and maintenance of the fibronectin-rich matrix. Anti-TNFalpha neutralizing antibody inhibits the inflammatory state of preadipocytes positioning TNFalpha as an important mediator of inflammation in preadipocytes. Strikingly, conditioned media produced by macrophages isolated from human adipose tissue exerted comparable effects with activated macrophages, i.e. decreased adipogenesis and increased inflammatory state in the preadipocytes. These data show that macrophage-secreted factors inhibit the formation of mature adipocytes, suggesting possible role in limiting adipose tissue expansion in humans.     

Mechanisms of macrophage activation in obesity-induced insulin resistance

Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration by and activation of macrophages in adipose tissue are causally linked to obesity-induced insulin resistance. Studies have shown, however, that alternatively activated macrophages taking residence in adipose tissue and liver perform beneficial functions in obesity-induced metabolic disease. Alternatively activated macrophages reduce insulin resistance in obese mice by attenuating tissue inflammation and increasing oxidative metabolism in liver and skeletal muscle. The discovery that distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance suggests that pathways controlling macrophage activation can potentially be targeted to treat these comorbidities of obesity. Thus, this Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues. The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism.     

Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance

Obesity is associated with a chronic inflammatory state characterized by adipose tissue macrophage infiltration and inflammation, which contributes to insulin resistance. The cholinergic antiinflammatory pathway, which acts through the macrophage α7-nicotinic acetylcholine receptor (α7nAChR), is important in innate immunity. Here we show that adipose tissue possesses a functional cholinergic signaling pathway. Activating this pathway by nicotine in genetically obese (db/db) and diet-induced obese mice significantly improves glucose homeostasis and insulin sensitivity without changes of body weight. This is associated with suppressed adipose tissue inflammation. In addition, macrophages from α7nAChR-/- [α7 knockout (α7KO)] mice have elevated proinflammatory cytokine production in response to free fatty acids and TNFα, known agents causing inflammation and insulin resistance. Nicotine significantly suppressed free fatty acid- and TNFα-induced cytokine production in wild type (WT), but not α7KO macrophages. These data suggest that α7nAChR is important in mediating the antiinflammatory effect of nicotine. Indeed, inactivating this pathway in α7KO mice results in significantly increased adipose tissue infiltration of classically activated M1 macrophages and inflammation in α7KO mice than their WT littermates. As a result, α7KO mice exhibit more severely impaired insulin sensitivity than WT mice without changes of body weight. These data suggest that the cholinergic antiinflammatory pathway plays an important role in obesity-induced inflammation and insulin resistance. Targeting this pathway may provide novel therapeutic benefits in the prevention and treatment of obesity-induced inflammation and insulin resistance.     

CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity

BACKGROUND/AIMS: Obesity is associated with a low-grade inflammation, insulin resistance, and macrophage infiltration of adipose tissue. The role of CC chemokines and their respective receptors in human adipose tissue inflammation remains to be determined. METHODS: sc and visceral adipose tissue of obese patients (body mass index 53.1 +/- 11.3 kg/m(2)) compared with lean controls (body mass index 25.9 +/- 3.8 kg/m(2)) was analyzed for alterations in inflammatory gene expression. RESULTS: Macrophage infiltration was increased in sc and visceral adipose tissue of obese patients as determined by increased mRNA expression of a macrophage-specific marker (CD68) and by elevated macrophage infiltration. Gene expression of CC chemokines involved in monocyte chemotaxis (CCL2, CCL3, CCL5, CCL7, CCL8, and CCL11) and their receptors (CCR1, CCR2, CCR3, and CCR5) was higher in sc and visceral adipose tissue of obese patients. Serum concentrations of the inflammatory marker IL-6 and C-reactive protein were elevated in obese patients compared with lean controls. Obese patients revealed increased insulin resistance as assessed by the homeostasis model assessment of insulin resistance index and reduced plasma adiponectin concentrations. Adipose tissue expression of many CC chemokines and their receptors in the obese group positively correlated with CD68 expression. CONCLUSION: Up-regulation of the CC chemokines and their respective receptors in adipose tissue occurs in human obesity and is associated with increased systemic inflammation.     

Macrophage functions in lean and obese adipose tissue

Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.     

Melatonin alleviates adipose inflammation through elevating α‐ketoglutarate and diverting adipose‐derived exosomes to macrophages in mice

Obesity is associated with macrophage infiltration and metabolic inflammation, both of which promote metabolic disease progression. Melatonin is reported to possess anti‐inflammatory properties by inhibiting inflammatory response of adipocytes and macrophages activation. However, the effects of melatonin on the communication between adipocytes and macrophages during adipose inflammation remain elusive. Here, we demonstrated melatonin alleviated inflammation and elevated α‐ketoglutarate (αKG) level in adipose tissue of obese mice. Mitochondrial isocitrate dehydrogenase 2 (Idh2) mRNA level was also elevated by melatonin in adipocytes leading to increase αKG level. Further analysis revealed αKG was the target for melatonin inhibition of adipose inflammation. Moreover, sirtuin 1 (Sirt1) physically interacted with IDH2 and formed a complex to increase the circadian amplitude of Idh2 and αKG content in melatonin‐inhibited adipose inflammation. Notably, melatonin promoted exosomes secretion from adipocyte and increased adipose‐derived exosomal αKG level. Our results also confirmed that melatonin alleviated adipocyte inflammation and increased ratio of M2 to M1 macrophages by transporting of exosomal αKG to macrophages and promoting TET‐mediated DNA demethylation. Furthermore, exosomal αKG attenuated signal transducers and activators of transduction‐3 (STAT3)/NF‐κB signal by its receptor oxoglutarate receptor 1 (OXGR1) in adipocytes. Melatonin also attenuated adipose inflammation and deceased macrophage number in chronic jet‐lag mice. In summary, our results demonstrate melatonin alleviates metabolic inflammation by increasing cellular and exosomal αKG level in adipose tissue. Our data reveal a novel function of melatonin on adipocytes and macrophages communication, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory disease.     

Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.     

Decreased infiltration of adipose tissue macrophages and amplified inflammation of adipose tissue in obese mice with severe acute pancreatitis

ObjectiveMacrophages are involved in obesity-associated inflammation and severe acute pancreatitis (SAP) development. However, the role of adipose tissue macrophages (ATMs) in obesity-related SAP has not been fully elucidated. We investigated the relationship between ATMs and inflammatory responses in SAP model mice fed a high-fat diet (HFD).MethodsSAP was induced in animal models via intraperitoneal injections of caerulein and lipopolysaccharide (LPS). SAP severity was evaluated, both morphologically and biochemically, and macrophage infiltration in the pancreas and epididymal adipose tissue was measured. We also analyzed apoptosis levels, polarization of the ATMs, and expression of inflammatory mediators in epididymal adipose tissue.ResultsObesity increased disease severity in SAP animals. Increased macrophage infiltration in the pancreas induced by SAP was found in both normal diet (ND)- and HFD-fed mice. Total ATM infiltration in epididymal adipose tissue was elevated by HFD, while a significant decrease in infiltration was observed in both the ND + SAP and HFD + SAP groups. The apoptosis levels of ATMs were reduced in the HFD group, but were markedly enhanced in both the ND + SAP and HFD + SAP groups compared to their respective control groups. Higher levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) were observed in the HFD + SAP than in the ND + SAP group. Increased proportion of M1 type ATMs was induced by both HFD and SAP.ConclusionsTotal ATM infiltration was decreased in epididymal adipose tissue of SAP animals. ATM polarization to the M1 type resulted in an amplified inflammatory response in obese mice with SAP.