scholarly journals Adipokines as Drug Targets in Diabetes and Underlying Disturbances

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Vinícius Andrade-Oliveira ◽  
Niels O.S. Câmara ◽  
Pedro M. Moraes-Vieira
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Drug Targets ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Therapeutic Implications ◽  
Insulin Resistant

Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

scholarly journals Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

2013 ◽  
Vol 15 (1) ◽  
Author(s):  
Charmaine S. Tam ◽  
Leanne M. Redman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Low Grade ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Proinflammatory Mediators ◽  
Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance

2007 ◽  
Vol 292 (5) ◽  
pp. E1433-E1440 ◽  
Author(s):  
Jinhui Zhang ◽  
Wendy Wright ◽  
David A. Bernlohr ◽  
Samuel W. Cushman ◽  
Xiaoli Chen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Epididymal Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Insulin Resistant ◽  
Obese Rats ◽  
Initial Activation ◽  
Adipose Cells ◽  
Classic Pathway

Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-α-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance.

scholarly journals CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

2017 ◽  
Vol 312 (4) ◽  
pp. E309-E325 ◽  
Author(s):  
Pia S. Petersen ◽  
Xia Lei ◽  
Risa M. Wolf ◽  
Susana Rodriguez ◽  
Stefanie Y. Tan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Resistance Index ◽  
Activity Level ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Metabolic Role ◽  
Obesity And Diabetes

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.

scholarly journals Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice

2018 ◽  
Vol 315 (4) ◽  
pp. E676-E693 ◽  
Author(s):  
Valentina Caracciolo ◽  
Jeanette Young ◽  
Donna Gonzales ◽  
Yingchun Ni ◽  
Stephen J. Flowers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Zinc Finger Protein ◽  
Inflammatory Responses ◽  
Adipose Tissue Inflammation ◽  
Obese Mice ◽  
Tissue Inflammation ◽  
Mrna Binding

Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet-induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKβ and the p65 subunit of NF-κB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice.

scholarly journals Adipose Tissue Remodeling as Homeostatic Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Michiko Itoh ◽  
Takayoshi Suganami ◽  
Rumi Hachiya ◽  
Yoshihiro Ogawa
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Inflammatory Responses ◽  
Saturated Fatty Acids ◽  
Tissue Remodeling ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Adipose Tissue Remodeling ◽  
Novel Therapeutic Strategies

Evidence has accumulated indicating that obesity is associated with a state of chronic, low-grade inflammation. Obese adipose tissue is characterized by dynamic changes in cellular composition and function, which may be referred to as “adipose tissue remodeling”. Among stromal cells in the adipose tissue, infiltrated macrophages play an important role in adipose tissue inflammation and systemic insulin resistance. We have demonstrated that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. Notably, saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 complex, thereby activating macrophages. Such a sustained interaction between endogenous ligands derived from parenchymal cells and pathogen sensors expressed in stromal immune cells should lead to chronic inflammatory responses ranging from the basal homeostatic state to diseased tissue remodeling, which may be referred to as “homeostatic inflammation”. We, therefore, postulate that adipose tissue remodeling may represent a prototypic example of homeostatic inflammation. Understanding the molecular mechanism underlying homeostatic inflammation may lead to the identification of novel therapeutic strategies to prevent or treat obesity-related complications.

Abstract 537: Dock2 Deficiency Mitigates High-Fat Diet-Induced Obesity by Reducing Adipose Tissue Inflammation While Increasing Energy Expenditure

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xia Guo ◽  
Feifei Li ◽  
Zaiyan Xu ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Inflammatory Diseases ◽  
Body Weight Gain ◽  
Public Health Problem ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation

Obesity is a public health problem as its association with type 2 diabetes, cardiovascular disorders and many other diseases. Adipose tissue inflammation is frequently observed and plays a vital role in obesity and insulin resistance. Dedicator of cytokinesis 2 (DOCK2) has shown proinflammatory effect in several inflammatory diseases, but its role in obesity remain unknown. To explore the function of DOCK2 in obesity and insulin resistance, wild-type (WT) and DOCK2 knockout (DOCK2-/-) mice were fed with chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical and histologic analyses were performed. DOCK2 expression was robustly up-regulated in adipose tissue in WT mice given HFD. DOCK2-/- mice were protected against HFD-enhanced body weight gain with an improved metabolic homeostasis and insulin resistance. In addition, DOCK2 deficiency attenuated adipose tissue and systemic inflammation accompanied by a reduced macrophage infiltration. Moreover, DOCK2 deficiency induced the adipose tissue browning and increased energy expenditure as shown by the up-regulation of metabolic genes in DOCK2-/- mice. Our data indicated that DOCK2 deficiency can protect mice from HFD-induced obesity, metabolic disorders, and insulin resistance. Therefore, targeting DOCK2 may be a potential therapeutic strategy for treating obesity-associated diseases.

scholarly journals Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans

2017 ◽  
Vol 117 (02) ◽  
pp. 286-294 ◽  
Author(s):  
Susanna Lallukka ◽  
Panu K. Luukkonen ◽  
You Zhou ◽  
Elina Isokuortti ◽  
Marja Leivonen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Liver Fat ◽  
Adipose Tissue Inflammation ◽  
Inflammatory Genes ◽  
Tissue Inflammation ◽  
Hepatic Expression ◽  
Insulin Resistant

SummaryIncreased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant (‘IR’) versus insulin-sensitive (‘IS’)] and PNPLA3 genotype (PNPLA3148MM/MI vs PNPLA3148II). Liver fat content (1H-MRS) was similarly increased in ‘IR’ (13 ± 1 %) and PNPLA3148MM/MI (12 ± 2 %) as compared to ‘IS’ (6 ± 1 %, p < 0.05) and PNPLA3148II (8 ± 1 %, p < 0.05), respectively. FVIII, FIX, FXIII, fibrinogen and VWF:RCo activities were increased, and PT and APTT shortened in ‘IR’ versus ‘IS’, in contrast to these factors being similar between PNPLA3148MM/MI and PNPLA3148II groups. In subjects undergoing a liver biopsy and entirely lacking the I148M variant, insulin-resistant subjects had higher hepatic expression of F8, F9 and FGG than equally obese insulin-sensitive subjects. Expression of pro-inflammatory genes in adipose tissue correlated positively with PT (% of normal), circulating FVIII, FIX, FXI, VWR:RCo and fibrinogen, and expression of anti-inflammatory genes negatively with PT (%), FIX and fibrinogen. We conclude that obesity/insulin resistance rather than an increase in liver fat is associated with a procoagulant plasma profile. This reflects adipose tissue inflammation and increased hepatic production of coagulation factors and their susceptibility for activation.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

Cytokine ◽  
2015 ◽  
Vol 75 (2) ◽  
pp. 280-290 ◽  
Author(s):  
Dov B. Ballak ◽  
Rinke Stienstra ◽  
Cees J. Tack ◽  
Charles A. Dinarello ◽  
Janna A. van Diepen
Keyword(s):  
Metabolic Disease ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Family Members ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Disease Focus
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