Sensitization of adipose tissue to insulin by rat serum

Summary The oxidation of the C-1 atom of glucose through the pentose shunt of adipose tissue, under maximal stimulation by insulin, was enhanced by rat serum. The material responsible for the increase of the efficacy of insulin by serum was ultrafiltrable and partly dialysable. At submaximal concentrations of insulin, the serum-induced enhancement of responses to insulin resulted in an increase of the relative potency of insulin (potentiation).Sodium acetate modified the log dose-response curve of insulin in the same way as serum did. Furthermore, acetate was active at low concentrations, suggesting that serum acetate might contribute to the sensitization to insulin by serum. In the presence of glucose and insulin, acetate is known to activate the rate of synthesis of fatty acids, which, in turn, determines the activation of the pentose shunt. Other constituents of serum known to influence the metabolism of adipose tissue in the same way as acetate may be expected to contribute to the sensitization to insulin by serum.Preliminary communication: Guidoux and Peters, 1970; Guidoux et al. 1972.Supported by Fonds National Suisse de la Recherche Scientifique, Grants No. 5316, 3.370.70 and 3.736.72.     

Neuropeptide - adipose tissue communication and intestinal pathophysiology

Until recently, fat was considered a relatively inactive tissue serving only as a depot for the storage of excess lipid around the body. Over the last decade, however, several studies have established fat as a metabolically active endocrine organ able to affect human pathophysiology at multiple levels. During this time adipose tissue has been shown to produce a number of hormones and inflammatory mediators collectively termed as adipokines. These molecules have been shown to be involved in the etiology of a number of inflammation-associated pathological conditions ranging from atherosclerosis and hypertension to diabetes and cancer. Despite the close physical association of abdominal fat and the intestine in the visceral cavity and the significant paracrine functions now attributed to adipose tissue, very little is known on the potential interactions between these tissues as they may relate to intestinal homeostasis. Considering the dramatic alterations in mesenteric fat depot size and placement during at least one intestinal disease, Crohn's disease, the potential involvement of fat tissue in the development as well as the progression of this and other pathological conditions should be considered. In this review we discuss the latest knowledge on neuropeptide-adipose tissue communication and the potential changes such interaction may induce in intra-abdominal fat tissue physiology. Finally we will discuss evidence on the potential pathways by which such changes in fat physiology may affect the development and progress of intestinal pathological conditions such as inflammatory bowel disease.     

Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes

Aims: To investigate the value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in a cohort of a community’s residents who were diagnosed as pre-diabetes, and to evaluate the association of VAT and SAT with insulin resistance.

Methods: This study was based on cross-sectional analysis of data from 107 adults. VAT and SAT were assessed by computed tomography. Insulin resistance was defined by homeostasis model assessment of insulin resistance >2.69. The relationship of VAT and SAT with insulin resistance were examined by linear regression. Logistic regression was used to analyze the association of VAT and SAT with insulin resistance.

Results: A total of 87 subjects had VAT ≥100?cm². Thirty-six out of 107 (33.6%) subjects were detected to have insulin resistance, 71 were normal (66.4%), and all had insulin resistance with VAT ≥100?cm². VAT (r?=?0.378, p?r?=?0.357, p?p?=?.003), but that of SAT was lost.

Conclusion: Pre-diabetic subjects with insulin resistance had elevated levels of VAT. VAT was more strongly associated with insulin resistance than SAT in Chinese subjects with pre-diabetes.     

JNK: bridging the insulin signaling and inflammatory pathway

Obesity and insulin resistance are strongly associated with systemic markers of inflammation and endoplasmic reticulum stress. c-Jun N-terminal kinases (JNK) are activated by inflammatory cytokines and have a key role in beta-cell apoptosis and in negative regulation of insulin signaling. JNK1-deficient mice are protected from diet-induced obesity and insulin resistance, while genetically obese mice with targeted mutations in JNK1 are leaner and have reduced insulin and blood glucose levels. These studies validate JNK as a link between inflammation and metabolic diseases and as a promising drug target. This review highlights recent advances in small-molecule inhibitors of JNK that have also been targeted for other diseases with an inflammatory component such as stroke, rheumatoid arthritis, and Alzheimer's and Parkinson's diseases.     

Role of brown adipose tissue in the thermal response to chlorpromazine in rats during cold exposure (author's transl)

Significance of the intercapsular brown adipose tissue (IBAT) in the thermal response to chlorpromazine (CPZ) during acute and chronic cold exposure was studied in rats. Adult male Wistar-Imamichi rats were exposed to 4 degrees C for 1 (cold-exposed) or 30 days (cold-acclimated). Intraperitoneal injection of 10 mg/kg CPZ caused a more marked and lasted hypothermia in acute cold-exposed rats as compared with that seen in control or in cold-acclimatized rats. Hypothermia induced by CPZ was unaffected by removal of IBAT either in control or acute cold-exposed rats. But in cold-acclimated rats, the removal of IBAT potentiated the hypothermia by CPZ. The relative weight of IBAT in cold-acclimated rats was about 3 times heavier than that in control and acute cold-exposed rats. CPZ had no effect on the relative weight of IBAT in all groups examined. Total lipids in IBAT showed no significant changes following CPZ administration in rats of all groups. In acute cold-exposed rats, serum FFA level progressively decreased after CPZ injection. The noradrenaline concentration in IBAT increased after chronic cold exposure and CPZ suppressed this elevation. The results suggest that the thermogenesis related sympathetic activity in the IBAT plays a mediatory role in thermal response to CPZ during cold acclimation.     

Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid.     

Role of SNARE's in the GLUT4 translocation response to insulin in adipose cells and muscle

Insulin stimulates glucose transport in skeletal muscle, heart, and adipose tissue by promoting the appearance of GLUT4, the major glucose transporter isoform present in these tissues, on the cell surface. This is achieved by differentially modulating GLUT4 exocytosis and endocytosis, between a specialized intracellular compartment and the plasma membrane. Ligands which activate the heterotrimeric GTP-binding proteins Gs and Gi appear to modulate insulin-stimulated glucose transport through effects on the fusion of docked GLUT4-containing vesicles with the plasma membrane. In insulin resistance states, reduced cellular GLUT4 levels in adipose cells fully account for the decreased glucose transport response to insulin in these cells. In contrast, although insulin-stimulated GLUT4 translocation is also impaired in muscle, total cellular levels of GLUT4 are not altered. The defect in muscle has been attributed to a GLUT4 trafficking problem and thus studies of this mechanism could provide clues as to the nature of the impairment. The movement of GLUT4-containing vesicles from an intracellular storage site to the plasma membrane and the fusion of docked GLUT4-containing vesicles with the plasma membrane are conceptually similar to some secretory processes. A general hypothesis called the SNARE hypothesis (soluble NSF attachment protein receptors where NSF stands for N-ethylmaleimide-sensitive fusion protein) postulates that the specificity of secretory vesicle targeting is generated by complexes that form between membrane proteins on the transport vesicle (v-SNARE's) and membrane proteins located on the target membrane (t-SNARE's). Several v- and t-SNARE's have been identified in adipose cells and muscle. VAMP2 and VAMP3/cellubrevin (v-SNARE's) have been shown to interact with the t-SNARE's syntaxin 4 and SNAP-23. The cytosolic protein NSF has the characteristic of binding to the v-/t-SNARE complex through its interaction with alpha-SNAP, another soluble factor. Furthermore, recent studies have demonstrated that VAMP2/3, syntaxin 4, SNAP-23, and NSF are functionally involved in insulin-stimulated GLUT4 translocation in adipose cells and thus are likely to be involved in the Gs- and Gi-mediated modulation of the glucose transport response to insulin as well. This review summarizes recent advances on the normal mechanism of GLUT4 translocation and discusses how this process could be affected in insulin resistant states such as type II diabetes.     

Markedly reduced white adipose tissue and increased insulin sensitivity in adcyap1-deficient mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide implicated in several metabolic functions, including insulin secretion and sympathoadrenal activation. To clarify the roles of PACAP in maintenance of whole-body glucose and lipid homeostasis, the impact of the deletion of PACAP on glucose homeostasis, body weight, and adipose tissue mass was examined by comparing mice lacking the Adcyap1 gene encoding PACAP (Adcyap1(-/-)) with wild-type littermate controls. Adcyap1(-/-) mice showed significant hypoinsulinemia, although being normoglycemic, and lower body weight as well as reduced food intake. They also showed greatly reduced white adipose tissue mass, in which the mRNA expression of adipocyte fatty acid-binding protein (aP2), a marker of adipocyte differentiation, was decreased. Glucose and insulin tolerance tests revealed increased insulin sensitivity in Adcyap1(-/-) mice. In accordance with these observations, plasma levels of resistin, an adipocytokine implicated in insulin resistance, were decreased in Adcyap1(-/-) mice. After a high-fat dietary challenge for six weeks, Adcyap1(-/-) mice still showed lower body weights and increased insulin sensitivity. These results indicate the crucial roles of PACAP in energy metabolism, including lipid metabolism, and in the regulation of body weight, raising the possibility that the PACAP-signaling pathway that favors energy storage could be a therapeutic target for obesity.     

Role and mechanism of ORM in adipose tissue fibrosis and insulin resistance in obese mice

OBJECTIVE During the development of obesity, adipose tissue fibrosis occurs as a hallmark of adipose tissue dysfunction, leading to metabolic dysfunction such as insulin resistance. We previously reported adipokine orosomucoid(ORM) could be a negative feedback signal in energy homeostasis, and its level was significantly elevated in response to obese state. Here we aimed to explore the role of ORM in adipose tissue fibrosis and insulin resistance during obesity, and its possible mechanism. METHODS MRI was used to assess the distribution of fat and the fat or lean mass in ORM1 knockout mice. HE staining, masson staining, qPCR, and Western blotting were used to assess the fibrosis status of mice. And we used glucose tolerance test(GTT) and insulin tolerance test(ITT) to evaluate the regulation of blood glucose and insulin sensitivity in mice. Leptin receptor-deficient db/db mice and high fat diet-induced obese mice were used as obese models. 3 T3-L1 cells were used in vitro. RESULTS ORM1-deficient mice exhibited an obese phenotype with adipose tissue fibrosis and insulin resistance. The m RNA and protein levels of the fibrogenic genes encoding Col1a1, Col3a1, Col6a3 and ECM regulators MMP-2, MMP-13, MMP-14 TIMP-1,TIMP-2, and TIMP-3 in ORM1-deficient mice were significantly increased. GTT and ITT showed abnormal glucose tolerance and insulin resistance in ORM1-deficient mice.Moreover, exogenous administration of ORM attenuated excessive expression of type Ⅵ collagen, MMP-13 and TIMP-1 induced by adipose fibrosis in obese db/db(lep Rdeficient) mice. GTT and ITT showed ORM treatment improved insulin resistance in db/db mice. Moreover,ORM synergized with insulin to activate Akt in adipose tissue of db/db mice. Further studies found that ORM could bind to C-C chemikine receptor 5(CCR5) and ORM improves insulin resistance in high fat diet-induced obese mice, which could be blocked by maraviroc, an antagonist against CCR5. In addition, the effect of ORM in synergy with insulin to activate Akt in adipose tissue of db/db mice was also abolished by maraviroc. We also found that ORM stimulated AMPK activity and inhibits the TGF-β_1 expression in adipose tissue of db/db mice,thereby attenuating adipose tissue fibrosis. In vitro, ORM treatment also alleviated abnormal expression of fibrogetic genes in 3 T3-L1 fibroblasts induced by TGF-β_1. Of note,the inhibitory effects of ORM on fibrosis were abolished by dorsomorphin, a selective inhibitor of AMPK. CONCLUSION ORM alleviates adipose tissue fibrosis and insulin resistance through CCR5. ORM is expected to be a novel target for the treatment of obesity and its related diseases.     

Neonatal monosodium-L-glutamate treatment reduced lipolytic response of rat epididymal adipose tissue

1. The effect of neonatal monosodium-L-glutamate (MSG) treatment on lipolysis in rat epididymal adipose tissue was studied. A reduction in the basal lipolysis was observed in the MSG-treated rats. 2. This was accompanied by a decrease lipolytic response to isoprenaline, adrenocorticotropic hormone, forskolin, isobutylmethylxanthine and dibutyryl-cAMP. 3. The addition of adenosine deaminase, which inactivates endogenous adenosine in the medium, did not normalize the basal and the hormone stimulated lipolytic responses. 4. The maximal lipolysis stimulated by adenosine deaminase or 8-(p-sulfophenyl)-theophylline (8-SPT), an adenosine antagonist, was significantly lower in the MSG-treated rats. 5. Moreover, there was no change in the sensitivity of adenosine receptors to its antagonist as reflected by the similar potency of 8-SPT in eliciting the lipolytic response in both the control and MSG-treated rats. 6. In conclusion, neonatal MSG treatment in rats induced a general reduction of lipolytic response in the epididymal adipocytes which cannot be explained by an enhancement of the adenosine inhibitory system.     

Changes in adipose tissue hormone-sensitive lipase activity and cAMP during ethanol withdrawal

The time course of the effects of ethanol withdrawal on brown and white adipose tissue hormone-sensitive lipase, cAMP production, and phosphodiesterase have been investigated after chronic drinking or liquid diet schedules. Chronic drinking significantly reduced brown adipose tissue hormone-sensitive lipase activity and cAMP levels from control. During withdrawal, there was a rebound increase to 200% control, peaking 9 h into withdrawal. White adipose tissue hormone-sensitive lipase activity and cAMP accumulation were significantly raised by both treatment schedules. Ethanol liquid diet produced a significant fall in adipose tissue hormone-sensitive lipase activity and cAMP accumulation. In brown fat, there was a rebound increase in hormone-sensitive lipase activity and cAMP; in white fat, no rebound was observed. In brown fat, the reductions in hormone-sensitive lipase activity and cAMP accumulation after chronic drinking coincided with an increase in phosphodiesterase activity. In white fat, the rise in cAMP and hormone-sensitive lipase activation coincided with a decrease in phosphodiesterase activity. We conclude that the effects of chronic ethanol on hormone-sensitive lipase activity are cAMP-dependent and mediated via alterations in phosphodiesterase activity.     

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.     

Review article: lymphatic system and associated adipose tissue in the development of inflammatory bowel disease

Background The lymphatic system plays critical roles in tissue fluid homoeostasis, immune defence and metabolic maintenance. Lymphatic vessels transport lymph, proteins, immune cells and digested lipids, allowing fluid and proteins to be returned to the blood stream, lipids to be stored and metabolized and antigens to be sampled in lymph nodes. Lymphatic drainage is mainly driven by rhythmic constrictions intrinsic to the vessels and critically modulated by fluid pressure and inflammatory mediators. Aim To collect and discuss the compelling available information linking the lymphatic system, adiposity and inflammation. Methods A literature search was performed through PubMed focusing on lymphatic system, inflammation, immune cells and fat transport and function in the context of IBD. Results Evidence collected allows us to propose the following working model. Compromised lymph drainage, reported in IBD, leads to oedema, lymphangiogenesis, impaired immune cell trafficking and lymph leakage. Lymph factor(s) stimulate adipose tissue to proliferate and produce cytokines, which affect immune cell functions and exacerbate inflammation. Conclusions Understanding the lymphatic system’s role in immune cell trafficking and immune responses, contribution to fat transport, distribution, metabolism and implication in the pathogenesis of chronic intestinal inflammation may provide the basis for new therapeutic strategies and improved quality‐of‐life.     

冰岛刺参岩藻聚糖硫酸酯对胰岛素抵抗小鼠炎症改善作用的研究

目的 研究冰岛刺参岩藻聚糖硫酸酯（fucoidan from the sea cucumber Cucumaria frondosa, Cf-FUC）对胰岛素抵抗小鼠炎症反应的改善作用。方法 以高脂高糖饲料饲喂法建立胰岛素抵抗小鼠模型。雄性C57BL/6J小鼠随机分为正常对照组、模型对照组、阳性对照组、Cf-FUC组。正常对照组饲喂标准饲料,其它组饲喂高脂饲料。阳性对照组、Cf-FUC组分别在饲料中添加罗格列酮（rosiglitazone, RSG, 1 mg?kg?1?d?1）、Cf-FUC (80 mg?kg?1?d?1）。各组小鼠自由摄食摄水19周。实验结束后,检测血清肿瘤坏死因子α（TNF-α）、MIP-1、IL-1β、IL-6和IL-10表达水平,荧光定量PCR方法检测小鼠脂肪组织炎症细胞因子基因mRNA表达水平,Western方法检测JNK1、IKKβ磷酸化蛋白水平及细胞核和细胞质中NFκB蛋白表达量。结果Cf-FUC可显著降低胰岛素抵抗小鼠血清TNF-α、MIP-1、IL-1β和IL-6浓度,增加IL-10浓度;抑制小鼠脂肪组织TNF-α、MIP-1、IL-1β和IL-6基因mRNA表达,促进IL-10基因mRNA表达;抑制JNK1和IKKβ的磷酸化,增加细胞质中NFκB蛋白表达量,减少细胞核中NFκB蛋白表达量。结论Cf-FUC能通过抑制JNK和IKKβ/NFκB信号通路抑制促炎症因子分泌,增加抑炎症因子分泌,改善胰岛素抵抗小鼠的炎症反应。     

Toxicogenomic study to identify potential signaling alterations related to nasal inflammatory damages induced by diesel exhaust particles in primary human nasal epithelial cells

In this study, we aimed to identify signaling alteration caused by exposure to diesel exhaust particles (DEPs) using primary human nasal epithelial cells (PHNECs). Global gene expression profiles in PHNECs following 50 and 200 μg/ml of DEP exposure were identified using microarray analysis. To cover the limitation of array-based mRNA expression analysis, text-mining-based software was used to analyze the integrative biological networks and relevant disease-focused functions among identified DEP-responsive genes. The confidence was valued based on the connectivity between the analyzed pathway and marker candidates. Through a literature-based pathway analysis, the stimulation of inflammation- and immune response-related processes mediated by TNF were predicted as major signaling alterations in PHNECs caused by DEP exposure. CSF3, CXCL8, MMP1, and VEGFA were identified as key hub genes in the predicted pathway. Significant expression level changes in the five key genes following DEP exposure were validated in terms of protein and mRNA expression. Although further studies are required, our toxicogenomic investigation provides key clues to the exact mechanism underlying DEP-induced nasal inflammatory damage. It also suggests an efficient approach for other research on adverse effects occurring in the upper respiratory tract following DEP exposure.     

Functional alterations of mesenteric vascular bed, vas deferens and intestinal tracts in a rat hindlimb unloading model of microgravity

1. Prolonged bed rest or exposure to microgravity may cause several alterations in autonomic nervous system response (ANSR). 2. Hindlimb unloading (HU) rats were used as an animal model of simulated microgravity to investigate ANSR changes. The experiments were carried out to investigate the effects of simulated microgravity on the autonomic nervous response of the perfused mesenteric vascular bed (MVB), vas deferens and the colon and duodenum from 2-week HU rats. 3. In MVB preparations of HU rats, the frequency-dependent increases in perfusion pressure with perivascular nerve stimulation (PNS; 8-40 Hz) were inhibited, whereas the noradrenaline (NA) concentration-dependent (1-100 microM) perfusion pressure increases were potentiated. The latter most probably reflected up-regulation of alpha-adrenergic receptor function. Relaxant responses of NA-precontracted MVB to PNS (4-30 Hz) or isoprenaline were not different between control and HU preparations, while vasodilation induced by the endothelial agonist ACh was reduced. 4. Transmural stimulation (2-40 Hz) induced frequency-dependent twitches of the vas deferens which were reduced in vas deferens of HU rats, while the sensitivity to NA-induced contraction was significantly increased. 5. In the gastroenteric system of HU rat, direct contractile responses to carbachol or tachykinin as well as relaxant or contractile responses to nervous stimulation appeared unchanged both in the proximal colon rings and in duodenal longitudinal strips. 6. In conclusion, HU treatment affects peripheral tissues in which the main contractile mediators are the adrenergic ones such as resistance vessels and vas deferens, probably by reducing the release of neuromediator. This study validates NA signalling impairment as a widespread process in microgravity, which may most dramatically result in the clinical phenotype of orthostatic intolerance.