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。     

Relation of depot-specific adipose inflammation to insulin resistance in human obesity

BACKGROUND:

A low-grade state of adipose tissue inflammation associated with obesity has been linked to mechanisms of systemic metabolic dysfunction. However, the relation of clinical phenotypes to depot-specific inflammation has not been well examined in human obesity.

OBJECTIVE:

To characterize the inflammatory status of subcutaneous and visceral fat depots, as assessed by tissue presence of macrophage crown-like structures (CLS) as a hallmark of chronic inflammation, and determine the relation of systemic insulin resistance to inflammatory abnormalities in subcutaneous and visceral fat.

METHODS:

We collected adipose tissue simultaneously from subcutaneous and visceral (omental and mesenteric) depots in 92 obese participants (age 42±11 years; BMI⩾30 kg m⁻²) during planned bariatric surgery. Using immunohistochemistry, we categorized individuals as CLS⁺ or CLS⁻ based on the presence or absence, respectively, of macrophage CLS in subcutaneous (CLS_s), omental (CLS_o) and mesenteric (CLS_m) adipose depots.

RESULTS:

The majority of participants exhibited adipose tissue inflammation manifest by the presence of CLS (CLS⁺) in both subcutaneous and intra-abdominal visceral depots. CLS status in subcutaneous fat was highly sensitive and modestly specific for inflammation of visceral fat. In multivariable models, plasma insulin and homeostatis model assessment levels were positively associated with CLS⁺ status in all depots independent of age, waist circumference, BMI and type 2 diabetes, and worsened with the increasing number of adipose regions involved.

CONCLUSIONS:

In severely obese participants, systemic insulin resistance is linked to adipose inflammation in both subcutaneous and visceral depots. The findings suggest that examination of subcutaneous regions that are more easily accessible by transcutaneous biopsy may prove useful in clinical studies designed to investigate adipose phenotypes in relation to human disease.     

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。     

Diet-induced adiposity alters the serum profile of inflammation in C57BL/6N mice as measured by antibody array

Morbid obesity is considered a systemic inflammatory state. The objective of this project was to characterize the adipokine, cytokine and chemokine protein profile in serum from control, lean and obese mice. We hypothesized that chemokines and cytokines are altered by caloric restriction and diet-induced obesity as a function of changes in body composition. Six-week-old female C57BL/6N mice (n = 12 per group) were randomized to one of three diets: control (fed ad libitum ); lean (30% calorie-restricted regimen relative to control) and diet-induced obese (DIO; high calorie diet, fed ad libitum ). Body weight, body composition and food intake were monitored throughout the study. After 10 weeks on the diets, blood samples were collected, and adipokine/cytokine/chemokine serum profiles were measured by antibody array. Lean mice, relative to the control group, displayed increased concentrations of insulin-like growth factor (IGF) binding protein-3, -5 and -6 and adiponectin and decreased IGF-1. These mice also showed increased concentrations of interleukin (IL)-10, IL-12 p40/p70, eotaxin, monocyte chemoattractant protein-5 and SDF-1. In contrast, DIO mice displayed increased leptin, IL-6 and LPS-induced chemokine and decreased concentrations of all chemokines/cytokines measured relative to control mice. As such, these data indicate that DIO may lead to an inflammatory state characterized as a shift towards a T helper lymphocyte type 1–skewed responsiveness. The demonstration of differential adipokine, cytokine and chemokine protein profile in control, lean and DIO mice may have implications for immune responsiveness and risk of disease.     

Inflamed adipose tissue, insulin resistance and vascular injury

Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall.     

Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance

In-vitro studies have implicated the A(1) adenosine receptor (A(1)AR) of adipocytes in inhibition of lipolysis, stimulation of lipogenesis and enhancement of the action of insulin on glucose metabolism. To determine whether any of these activities were physiologically relevant in an intact animal, A(1)AR was overexpressed in adipose tissue of transgenic mice. Lower plasma free fatty acid (FFA) levels were observed in the transgenic mice relative to the litter-matched controls, supporting a significant physiological role for adipocyte A(1)AR in the control of lipolysis. However, no differences were observed in body weights or body composition. On a high fat diet, both the transgenic mice and the litter matched controls, male and female, became equally obese. Unlike the control mice, however, the transgenic mice did not develop insulin resistance, as demonstrated by serum glucose and insulin levels and glucose and insulin tolerance tests. These findings demonstrate that adipocyte A(1)AR plays an important physiological role in the control of insulin sensitivity in an intact animal and therefore should be considered to be a potential therapeutic target for the treatment of obesity-related insulin resistance and type 2 diabetes.     

Blockade of kinin B(1) receptor reverses plasma fatty acids composition changes and body and tissue fat gain in a rat model of insulin resistance

Aim: Kinin B₁ receptor (B₁R) contributes to insulin resistance through a mechanism involving oxidative stress. This study examined the effect of B₁R blockade on the changes in plasma fatty acids composition, body and tissue fat mass and adipose tissue inflammation that influence insulin resistance. Methods: Sprague–Dawley rats were fed with 10% D‐glucose or tap water (Control) for 13 weeks and during the last week, rats were administered the B₁R antagonist SSR240612 (10 mg/kg/day, gavage) or vehicle. The following parameters were assessed: plasma fatty acids (by gas chromatography), body composition (by EchoMRI), metabolic hormone levels (by radioimmunoassay), expression of B₁R and inflammatory markers in adipose tissue (by Western blot and qRT‐PCR). Results: Glucose feeding significantly increased plasma levels of glucose, insulin, leptin, palmitoleic acid (16:1n‐7), oleic acid (18:1n‐9), Δ6 and Δ9 desaturases while linoleic acid (18:2n‐6), arachidonic acid (20:4n‐6) and Δ5 desaturase were decreased. SSR240612 reduced plasma levels of insulin, glucose, the homeostasis model assessment index of insulin resistance, palmitoleic acid and n‐7 family. Alterations of Δ5, Δ6 and Δ9 desaturases were normalized by SSR240612. The B₁R antagonist also reversed the enhancing effect of glucose feeding on whole body and epididymal fat mass and on the expression of macrophage CD68, interleukin‐1β, tumour necrosis factor‐α and inducible nitric oxide synthase in retroperitoneal adipose tissue. B₁R protein and mRNA were not detected in retroperitoneal adipose tissue. Conclusion: Insulin resistance in glucose‐fed rats is associated with low state inflammation in adipose tissue and plasma fatty acids changes which are reversed by B₁R blockade. These beneficial effects may contribute to insulin sensitivity improvement and the prevention of obesity.     

Vitamin D deficiency in the aetiology of obesity‐related insulin resistance

The obese insulin‐resistant state is often associated with low circulating concentration of vitamin D 25‐hydroxyvitamin D₃ [25(OH)D₃]. Fat sequestration of vitamin D in the expanded obese adipose tissue mass has been pointed out as a plausible explanation for this circulating vitamin D deficiency. However, the putative mechanisms behind this hypovitaminosis D remain to be elucidated. The presence of vitamin D receptor and vitamin D–metabolizing enzymes in insulin‐sensitive organs suggests that vitamin D may be involved in glucose and lipid metabolism and may be related to insulin sensitivity. Indeed, mainly in vitro studies support a role of vitamin D in regulating glucose and lipid metabolism in several insulin‐sensitive tissues including adipose tissue, skeletal muscle, liver, as well as pancreatic insulin secretion. A potential role of vitamin D in gut barrier function and metabolism has also been suggested. This review summarizes recent knowledge on vitamin D deficiency in the aetiology of obesity‐related insulin resistance and discusses potential underlying mechanisms. Finally, the role of vitamin D supplementation on insulin sensitivity and glycaemic control is discussed.     

Hypofibrinolysis in the insulin resistance syndrome: implication in cardiovascular diseases

Insulin resistance syndrome (IRS) is associated with increased cardiovascular morbidity and mortality. IRS is becoming one of the major health problems as its prevalence grows rapidly. Accelerated atherothrombotic process in the IRS is attributed to metabolic abnormalities, inflammation and to impaired fibrinolysis due to increased plasma plasminogen activator inhibitor type 1 (PAI-1) levels. Proinflammatory cytokines may have an important role in PAI-1 overexpression, particularly in the adipose tissue. Studies in genetically modified mice indicate that PAI-1 might be involved in the aetiopathogenesis of obesity. Modifying PAI-1 expression by PAI-1 inhibitors may open a new field of research and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes.     

Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance

Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system and acts as the major underlying mechanism for the development of obesity-associated diseases, notably insulin resistance and type 2 diabetes. Innate-like B cells are a subgroup of B cells that respond to innate signals and modulate inflammatory responses through production of immunomodulatory mediators such as the anti-inflammatory cytokine IL-10. In this study, we examined innate-like B cells in visceral white adipose tissue (VAT) and the relationship of these cells with their counterparts in the peritoneal cavity and spleen during diet-induced obesity (DIO) in mice. We show that a considerable number of innate-like B cells bearing a surface phenotype distinct from the recently identified “adipose natural regulatory B cells” populate VAT of lean animals, and that spleen represents a source for the recruitment of these cells in VAT during DIO. However, demand for these cells in the expanding VAT outpaces their recruitment during DIO, and the obese environment in VAT further impairs their function. We further show that removal of splenic precursors of innate-like B cells through splenectomy exacerbates, whereas supplementation of these cells via adoptive transfer ameliorates, DIO-associated insulin resistance. Additional adoptive transfer experiments pointed toward a dominant role of IL-10 in mediating the protective effects of innate-like B cells against DIO-induced insulin resistance. These findings identify spleen-supplied innate-like B cells in VAT as previously unrecognized players and therapeutic targets for obesity-associated diseases.The current obesity epidemic has led to an increase in the incidence of a variety of disorders that are collectively referred to as obesity-associated diseases. Changes in diet and lifestyle, especially the abundance of energy-dense high-fat foods, have played a central role in the emergence of this epidemic. Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system. This chronic inflammation acts as the major underlying mechanism for the development of obesity-associated diseases, notably insulin resistance and type 2 diabetes (T2D) (1–5). Both the innate and adaptive branches of the immune system are activated during obesity and participate in the induction and maintenance of obesity-triggered inflammation (1–7). In metabolic organs, most notably visceral white adipose tissue (VAT), increases in proinflammatory cells and decreases in anti-inflammatory cells create an insulin-antagonizing environment that interferes with normal metabolic pathways (1–5). Whereas it is now clear that multiple immune cells play a role in this process, the full spectrum of cellular and molecular signals that initiate and sustain the chronic inflammation in obesity remains to be delineated.Lymphocytes of the T- and B-cell lineages are traditionally categorized as components of the adaptive immune system, as they recognize specific pathogen-derived antigens and are capable of developing long-lasting immune memory. Among these conventional adaptive lymphocytes, CD8⁺ T cells and follicular (B-2) B cells have been shown to exacerbate, whereas CD4⁺Foxp3⁺ regulatory T (T_reg) cells have been shown to protect against, obesity-triggered inflammation and insulin resistance (8–11). Over the past few decades, a growing family of lymphocyte subsets with innate-like properties and functions has been identified (12–17). These cells, through recognition of nonspecific innate immune signals and production of immunomodulatory cytokines, interact with and influence the function of multiple cell types of the innate and adaptive branches of the immune system and thus shape subsequent immune and inflammatory responses and impact disease outcomes. In the T-cell lineage, several research groups have investigated the role of natural killer T (NKT) cells in obesity and insulin resistance (18). A recent report identified a subset of B cells in white adipose tissue that expressed a unique surface phenotype and protected mice against obesity-induced inflammation (19). However, whether other subsets of innate-like B cells capable of influencing insulin sensitivity also populate VAT is currently unknown. Additionally, the source(s) for the recruitment of these cells in VAT during obesity remains unclear.Several subsets of innate-like B cells, including B-1a and B-1b B cells, marginal zone (MZ) B cells, regulatory B cells, and innate response activator (IRA) B cells have been identified in lymphoid organs and in peritoneal cavity (PerC) of mice (12, 14–16, 19–21). These innate-like B-cell subsets share several phenotypic and functional characteristics but also display important differences. Compared with conventional adaptive B-2 B cells, innate-like B cells exhibit increased responsiveness to innate signals through a variety of innate receptors such as toll-like receptors (TLRs) (12, 14–16, 20, 21). Although these cells only constitute a small subpopulation of B cells in spleen and mainly reside in the PerC under steady-state conditions (12), adult mouse spleen houses progenitors and precursors of these cells and this organ therefore plays a critical role in maintaining a functional pool of innate-like B cells (22–24). Among innate-like B cells, IL-10–producing B cells, often referred to as regulatory B cells or B10 cells, modulate inflammatory responses primarily through production of the anti-inflammatory cytokine IL-10 (14–16). Furthermore, B-1a B cells are an important source of natural IgM antibodies that protect against atherosclerosis, a chronic inflammatory disease that shares several mechanistic features with obesity-associated diseases (25, 26).Several recent studies are consistent with a protective role of spleen-derived IL-10–producing B cells in obesity-induced inflammation and insulin resistance. Removal of spleen in diet-induced obesity (DIO) mice exacerbated VAT inflammation, which could be ameliorated by supplementation of IL-10 (27). Unfractionated B cells of DIO mice and of patients with T2D produced reduced levels of IL-10 in response to in vitro stimulation (10, 28). Whereas these findings suggest a critical role of spleen for provision of IL-10, possibly through IL-10–producing B cells, in protecting against obesity-associated insulin resistance, the cellular mechanisms of action remain unclear.We show here that a substantial number of B cells with a surface phenotype resembling innate-like B-1a and regulatory B10 B cells (12, 16, 29) but distinct from recently identified “adipose natural regulatory B cells” (19) populate VAT under steady-state conditions. Similar to their counterparts in spleen and PerC, these cells in VAT spontaneously produce IgM antibodies and constitute the majority of IL-10–competent B cells at this anatomic location. Whereas the spleen supports a pool of innate-like B cells in VAT, the demand for these cells in the expanding VAT during DIO outpaces their recruitment and the obese environment in VAT further impairs their IL-10 competence. Consequently, splenectomy exacerbates, whereas supplementation with these innate-like B cells via adoptive transfer ameliorates, DIO-induced systemic insulin resistance. Overall, our findings have identified a previously unrecognized subset of IL-10–competent innate-like B cells in VAT and provided evidence for a critical role of spleen in supplying these cells to VAT for protection against obesity-associated insulin resistance.     

Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance

Background and Objectives:

High fructose corn syrup (HFCS) is the most commonly used sweetener in the United States. Some studies show that HFCS consumption correlates with obesity and insulin resistance, while other studies are in disagreement. Owing to conflicting and insufficient scientific evidence, the safety of HFCS consumption remains controversial.

Subjects/Methods:

We investigated the metabolic consequences of mice fed a (a) regular diet, (b) ‘Western'' high-fat diet or (c) regular diet supplemented with 8% HFCS in drinking water (to mimic soft drinks) for 10 months. Adipose tissue macrophages (ATMs) have emerged as a major pathogenic factor for obesity and insulin resistance. ATMs consist of proinflammatory F4/80⁺CD11c⁺ macrophages and anti-inflammatory F4/80⁺CD11c⁻ macrophages. In this study, we assessed the effects of HFCS on ATMs in intra-abdominal fat.

Results:

We found that HFCS feeding in mice induced more severe adipose inflammation and insulin resistance than even the higher-calorie-containing ‘Western'' high-fat diet, and these HFCS-induced deleterious effects were independent of calorie intake or body fat content. We showed that similar to ‘Western'' high-fat diet, HFCS triggered a robust increase of both proinflammatory ATMs and anti-inflammatory ATMs in intra-abdominal fat. Remarkably, however, the anti-inflammatory ATMs were much less abundant in HFCS-fed mice than in high-fat-fed mice. Furthermore, we showed that deletion of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) ameliorates HFCS-induced adipose inflammation and insulin resistance. HFCS-fed GHS-R-null mice exhibit decreased proinflammatory ATMs in intra-abdominal fat, reduced adipose inflammation and attenuated liver steatosis.

Conclusion:

Our studies demonstrate that HFCS has detrimental effects on metabolism, suggesting that dietary guidelines on HFCS consumption for Americans may need to be revisited. GHS-R deletion mitigates the effects of HFCS on adipose inflammation and insulin resistance, suggesting that GHS-R antagonists may represent a novel therapy for insulin resistance.