Phytochemicals and their impact on adipose tissue inflammation and diabetes

Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too.In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo.     

Allergen exposure induces inflammation and affects adiponectin levels in adipose tissue

This study investigates whether allergen exposure elevates the risk of diabetes or cardiovascular diseases using acute OVA (Ovalbumin) allergen exposure model. We hypothesize that exposure to allergen can induce adipose tissue inflammation and affect adiponectin levels. An intranasal challenge with OVA male C57BL/6 mice was performed at dose of 6.25, 12.5, 25, 50 and 100 μg, and compared to which challenge with PBS (phosphate buffered saline). Results showed that acute OVA exposure did not only cause airway inflammation in study mice, but also decreased serum adiponectin levels with a dose-response effect. When examining the gonadal adipose tissues, there was no significantly difference of adiponectin mRNA in OVA challenged mice compared to those PBS challenged, but lower inguinal adiponectin mRNA expression was found compared to those PBS-challenged, and had a good relationship with the serum adiponectin. Inguinal adipose tissues of OVA challenged mice, had significantly lower adipose tissue weight, and higher TNF-α expression without statistical significance. Our data indicate that acute OVA exposure appears to affect the characteristics of adipose tissues, and change the adiponectin levels in serum and adipose tissues. Allergen exposure may be considered a potential risk factor for presenting diabetes or cardiovascular diseases.     

Systematic review: adipose tissue, obesity and gastrointestinal diseases

BACKGROUND: Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. Insulin resistance is the most widely accepted link between obesity and disease, particularly colorectal cancer. The recognition that intra-abdominal fat is immunologically active sheds new light not only on the pathogenesis of obesity-related gastrointestinal conditions, but also on inflammatory conditions such as Crohn's disease. AIM: To describe the biology of adipose tissue, its impact on the immune system and explores the possible underlying mechanisms linking obesity to gastrointestinal diseases. It also looks at the role of mesenteric fat in determining severity and course of Crohn's disease. METHODS: Relevant English-language literature and abstracts cited on MEDLINE database were reviewed. RESULTS: Our recent finding of an association between obesity and subclinical bowel inflammation suggests that, apart from promoting generalized immune activation, fat also evokes local immune responses. We propose that the proinflammatory milieu promoted by obesity could underlie many of these associations and that the mechanism implicating insulin resistance may merely represent an epiphenomenon. In Crohn's disease, on the other hand, intra-abdominal fat may provide a protective mechanism. CONCLUSION: The potential of adipose tissue as a therapeutic target is vast and needs exploration.     

The contribution of adipose tissue and adipokines to inflammation in joint diseases

Adipokines are proteins produced by white adipose tissue, which is an active secretory organ. Regulation of immune and inflammatory responses is among the multiple physiological processes involving adipokines. Leptin, adiponectin and resistin are the most extensively studied adipokines. Leptin may promote inflammation by inducing Th1 phenotype development, whereas adiponectin may combat inflammation by reducing the production of pro-inflammatory cytokines. Resistin belongs to a family of proteins found in foci of inflammation, where they contribute to the inflammatory response. All three adipokines have been detected in synovial fluid from joints affected with the inflammatory disease rheumatoid arthritis (RA) or the degenerative disease osteoarthritis (OA). Recent evidence points to involvement of leptin in RA and OA and indicates that adiponectin and/or resistin mediate inflammation in arthritis. Thus, fat tissue is an active organ whose products contribute to inflammatory and degenerative processes underlying common joint diseases.     

Regulation of stem cell differentiation in adipose tissue by chronic inflammation

1. Recent studies suggest that a local hypoxic response leads to chronic inflammation in the adipose tissue of obese individuals. The adipose tissue hypoxia may reflect a compensatory failure in the local vasculature system in response to obesity. 2. Studies suggest that inflammation stimulates angiogenesis and inhibits adipocyte activities in a feedback manner within the obese adipose tissue. Adipose-derived stem cells (ASC) are able to differentiate into multiple lineages of progenitor cells for adipocytes, endothelial cells, fibroblasts and pericytes. Differentiation of ASC into those progenitors is regulated by the adipose tissue microenvironment. 3. As a major factor in the microenvironment, inflammation may favour ASC differentiation into endothelial cells through the induction of angiogenic factors. At the same time, inflammation inhibits ASC differentiation into adipocytes by suppressing peroxisome proliferator-activated receptor γ activity and the insulin signalling pathway. In this context, inflammation may serve as a signal mediating the competition between adipocytes and endothelial cells for the limited source of ASC. 4. It is a new concept that inflammation mediates signals in the competition between adipocytes and endothelial cells for the limited ASC in obesity. There is a lot of evidence that inflammation promotes endothelial cell differentiation. However, this activity of inflammation remains to be established in adipose tissue. The present article reviews the literature in support of this conclusion.     

In vivo imaging of neuroinflammation

We briefly outline the rationale for employing positron emission tomography (PET), using the ligand [¹¹C](R)-PK11195, the binding site for which is highly expressed by activated microglia, in order (a) to detect in vivo neuroinflammatory changes occurring in a variety of brain diseases and at different disease stages and (b) to monitor the progression of neuroinflammation as a generic in vivo marker of ‘disease activity’. The use of [¹¹C](R)-PK11195 PET is described as a systematic attempt at measuring the emerging phenomenology of tissue pathology itself—as opposed to measuring, for example, the loss of neuronal function or structure—and as a proof of principle for the clinical utility of imaging glial cells in vivo.     

9-羟基利培酮的体内过程

9-羟基利培酮是非典型抗精神病药利培酮的主要活性代谢产物,其药理活性是母药的70%,比母药有更长的半衰期和更高的稳态血药浓度.帕潘利酮(利培酮缓释片)与利培酮片在整体疗效无明显差异,但是帕潘利酮能更有效地改善精神分裂症患者的社会功能,为此本文介绍了关于其体内过程(分布、代谢和排泄)的研究.     

In vivo alpha 2-adrenoceptor-mediated inhibition of isoproterenol-stimulated free fatty acid output in dog bone marrow adipose tissue

Clomdine, an α₂ agonist, inhibited the isoproterenol-induced free fatty acid outflow from perfused bone marrow adipose tissue of dog tibia. This effect was suppressed by the α₂-antagonist, yohimbine. These in vivo experiments clearly demonstrate an α₂-adrenoceptor-mediated inhibition of isoproterenol-induced lipid mobilization and argue for a physiological interplay between β- and α₂-site stimulation in the regulation of lipolysis.     

杠柳毒苷在大鼠体内的组织分布

目的 考察杠柳毒苷在大鼠体内的组织分布.方法 采用高效液相色谱法测定大鼠静脉注射杠柳毒苷后,组织样品中杠柳毒苷的质量浓度.结果 大鼠iv杠柳毒苷0.74 mg/kg,2、10、20 min后肝中杠柳毒苷的质量浓度分别为(2.447±0.687)、(0.6310±0.272)、(0.2924±0.228)μg/g,在肝中...     

Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity

Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of "M1" or "classically activated" macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to "M2" or an "alternatively activated" anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes.     

In vivo hydroquinone exposure impairs allergic lung inflammation in rats

Hydroquinone (HQ) is naturally found in the diet, drugs, as an environmental contaminant and endogenously generated after benzene exposure. Considering that HQ alters the immune system and its several source of exposures in the environment, we hypothesized that prolonged exposure of HQ could affect the course of an immune-mediated inflammatory response. For this purpose, male Wistar rats were intraperitoneally exposed to vehicle or HQ once a day, for 22 days with a 2-day interval every 5 days. On day 10 after exposure with vehicle or HQ, animals were ovalbumin (OA)-sensitized and OA-aerosolized challenged on day 23. HQ exposure did not alter the number of circulating leukocytes but impaired allergic inflammation, evidenced by lower number of leukocytes in the bronchoalveolar lavage fluid 24h after OA-challenge. Reduced force contraction of ex vivo tracheal segments upon OA-challenge and impaired mesentery mast cell degranulation after in situ OA-challenge were also detected in tissues from HQ exposed animals. The OA-specificity on the decreased responses was corroborated by normal trachea contraction and mast cell degranulation in response to compound 48/80. In fact, lower levels of circulating OA-anaphylactic antibodies were found in HQ exposed rats, as assessed by passive cutaneous anaphylaxis assay. The reduced level of OA-anaphylactic antibody was not dependent on lower number or proliferation of lymphocytes. Nevertheless, lower expression of the co-stimulatory molecules CD6 and CD45R on OA-activated lymphocytes from HQ exposed rats indicate the interference of HQ exposure with signaling of the humoral response during allergic inflammation. Together, these data indicate specific effects of HQ exposure manifested during an immune host defense.     

Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue

A small amount of adipose tissue associated with small arteries and arterioles is encountered both in mice and man. This perivascular adipose tissue (PVAT) has a paracrine effect on the vascular tone regulation. PVAT is expanded in obesity and in diabetes. This expansion not only involves enlargement of fat cells, but also the accumulation of inflammatory cells and a shift in the production of adipokines and cytokines. This effect is illustrated in this review by the effect of PVAT-derived factors of insulin-mediated vasoregulation in mouse resistance arteries. Insulin sensitivity of endothelial cells is also involved in the insulin-mediated regulation of muscle glucose uptake. Insulin affects vasoregulation by acting on different signaling pathways regulating NO and endothelin-1 release. This process is influenced by various adipokines and inflammatory mediators released from PVAT, and is affected by the degree of expansion and content of inflammatory cells. It is modulated by adiponectin (via 5' adenosine monophosphate-activated protein kinase, AMPK), TNFα (via c-jun N-terminal kinase) and free fatty acids (via protein kinase C-θ). PVAT thus provides an important site of control of vascular (dys)function in obesity and type 2 diabetes. An altered profile of adipokine and cytokine production by PVAT of resistance arteries may also contribute to or modulate hypertension, but a causal role in hypertension has still to be established.     

Comparison of in vivo bioluminescence imaging and lavage biomarkers to assess pulmonary inflammation

Gram-negative bacterial endotoxin triggers innate immunity via TLR-4 and NF-kB signal activation. The aim of this study was to evaluate the use of transgenic mice expressing luciferase as a marker of NF-kB activation for exploring innate immune responses to pulmonary endotoxin exposure over time thus obviating the need for serial necropsies. Transgenic rNF-kB-Luc BALB/c mice were exposed to two different types of endotoxin (Neisseria meningitidis lipooligosaccharide, and Escherichia coli lipopolysaccharide) at multiple doses by nasal instillation. Bioluminescence was quantified in vivo at five time points in three separate experiments. In the fourth experiment lungs were imaged ex vivo 8h post exposure and tissue was analyzed for luciferase activity. Non-transgenic BALB/c mice were similarly exposed to lipooligosaccharide and bronchoalveolar lavage was assessed for neutrophil recruitment and IL-6. Non-transgenic BALB/c mice exhibited highly significant increases of IL-6 and neutrophils in bronchoalveolar lavage 4h after the exposure to instilled doses as low as 30EU/mouse. In contrast, luciferase imaging of NF-kB signal activation in vivo in transgenic rNF-kB-Luc mice did not show significant changes over time or over doses from 30EU to 300,000EU/mouse of nasally-instilled endotoxin. Ex vivo lung imaging 8h after endotoxin exposure to 3000EU demonstrated a strong signal. An intravenous LPS dose of 300,000EU/mouse produced a measurable luminescence signal in vivo. This non-terminal assessment method is useful only with extremely high doses of endotoxin that induce systemic injury and cannot be applied to research of occupational and environmental exposures at relevant levels of endotoxin.     

A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.

1. Possible nitric oxide (NO)-mediated effects on lipolysis were investigated in vivo in human subcutaneous adipose tissue using microdialysis, as well as in vitro on isolated fat cells of non-obese, healthy volunteers. NO donors were added to the ingoing dialysate solvents. 2. Changes in lipolysis and local blood flow were investigated by measuring glycerol levels and ethanol ratios, respectively, in the microdialysates. 3. It was shown that the NO synthase inhibitor, N(G)-monomethyl L-arginine (L-NMMA), but not the biologically inactive enantiomer N(G)-monomethyl D-arginine (D-NMMA), increased glycerol levels in the microdialysates without causing a change of local blood flow. In addition, L-NMMA increased glycerol levels in the microdialysate when local blood flow was stimulated with hydralazine. 4. Nitric oxide gas as well as the NO donor, nitroglycerine, reduced glycerol release from isolated adipocytes in vitro. 5. Expression of inducible nitric oxide synthase (iNOS) in human adipose tissue was shown by Western blot analysis. Biologically active NOS was demonstrated by measuring total enzymatic activity. 6. In conclusion, the data demonstrate that inhibition of NO release in subcutaneous adipose tissue results in an increased lipolysis in vivo. These effects, which were also observed in vitro, are independent of local blood flow changes. Furthermore, the demonstration of enzymatic NOS activity and the expression of inducible nitric oxide synthase (iNOS) in adipose tissue indicate that locally synthesized NO may play a role in the physiological control of lipolysis in human adipose tissue.     

In vivo imaging of oligonucleotides with nuclear tomography

Positron emission tomography (PET) and single photon emission tomography (SPECT) are high-resolution, sensitive, molecular and functional imaging techniques that permit repeated, noninvasive assessment and quantification of specific biological and pharmacological processes in humans. PET and SPECT are also the most advanced technologies currently available for studying in vivo molecular interactions and therefore can advantageously play a key role in both drug discovery and development of pharmaceuticals, by assessing their in vivo distribution, pharmacokinetics, and dynamics, once labeled with a positron or gamma-emitter. Recent advances in positron and gamma-emitter labeling of bioconjugates allow the design and development of complex high-molecular-weight bioactive chemical structures as radiopharmaceuticals including single-stranded oligonucleotides. Besides, the introduction of high-resolution tomographic devices for imaging the distribution of radioactivity in small animal models such as mice and rats offers a unique opportunity to study the biological behavior of labeled compounds in integrated, unperturbed living systems. The present review illustrates the current technologies for labeling oligonucleotides with various radioisotopes, and their use as in vivo probes of oligonucleotide distribution and molecular interactions in target tissues. Emphasis will be also given to the role which could be played by these technologies in the development of oligonucleotide-based drugs.     

In vivo imaging of retinal ganglion cell apoptosis

1. Download : Download high-res image (154KB)
2. Download : Download full-size image

Highlights► Early diagnosis of glaucoma remains a clear and unmet need. ► Apoptosis of RGCs has been identified as the earliest form of cell loss in glaucoma. ► DARC and capQ can be used for single apoptotic cell resolution imaging in vivo. ► DARC will soon be tested in a glaucoma Phase I clinical trial.     

Pyrazolone derivative C29 protects against HFD-induced obesity in mice via activation of AMPK in adipose tissue

Beige adipocytes have been considered as a potential strategy in anti-obesity therapy because of its thermogenic capacity. AMP-activated protein kinase (AMPK) plays important roles in regulating adipose tissue function. C29 is a novel pyrazolone derivative with AMPK activity. In the current study, we investigated the role of C29 in the regulation of thermogenesis using differentiated adipocytes and diet-induced obese mice, and explored the mechanisms that might be involved in energy expenditure via adipocyte AMPK activation. We showed that treatment with C29 (2.5–10 μM) concentration-dependently increased thermogenesis in differentiated preadipocytes separated from inguinal white adipose tissue (iWAT), evidenced by increased expression levels of thermogenesis markers such as Ucp1, Pgc-1α, Dio2, Prdm16, Cox7a1, Cox8b, Elovl3, and Cidea, fatty acid oxidation (FAO) genes including Cpt1a, Lcad and Pparα, as well as beige-selective genes such as Cd137, Tmem26, Slc27a1, and Tbx1. In high-fat diet (HFD)-fed mice, oral administration of C29 (30 mg·kg⁻¹·day⁻¹) for 9 weeks alleviated HFD-induced obesity, promoted energy expenditure and modulated iWAT browning. However, these effects were not observed in adipose-specific AMPKα1/α2 knockout (AKO) mice following C29 administration. Together, this study demonstrates that C29 regulates energy balance via adipocyte AMPK. Our findings show that the discovery of AMPK activators that specifically target adipose tissue may have therapeutic potential for treating obesity-related metabolic diseases.     

肥胖SD 幼鼠脂肪组织血红素加氧酶-1 表达与炎症状态和抗炎机制的探讨

摘要：目的探讨肥胖SD 幼鼠内脏脂肪组织中血红素加氧酶（HO）-1 表达的变化及其与脂肪组织巨噬细胞浸润、极化间的关系。方法3 周龄雄性SD 大鼠24 只,随机均分为对照组和实验组,分别给予标准饮食和高脂饮食,喂养至7 周龄,检测三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、空腹血糖及胰岛素水平,定量PCR 检测肾周脂肪组织中HO-1、白介素（IL）-6、IL-10、单核细胞趋化蛋白（MCP）-1 基因表达变化,F4/80、CD206 免疫组化观察脂肪组织中巨噬细胞浸润和极化情况。结果实验组幼鼠已经存在空腹血糖和胰岛素升高,胰岛素抵抗情况明显,HO-1 表达明显高于对照组,炎症因子IL-6、MCP-1 基因表达明显高于对照组,抗炎症因子IL-10 低于对照组,差异有统计学意义（P＜0.05）。实验组巨噬细胞浸润明显多于对照组（P＜0.05）,实验组F4/80 免疫组化平均光密度（MOD）值与 CD206 免疫组化MOD 值差异无统计学意义（P＞0.05）。结论肥胖幼年SD 大鼠的内脏脂肪组织出现炎症反应,伴有HO-1 反应性的增加,后者影响巨噬细胞极化起到抗炎作用。