Adiponectin and other Adipocytokines as Predictors of Markers of Triglyceride-Rich Lipoprotein Metabolism

Abstract Background: Adipocytokines are bioactive peptides that may play an important role in the regulation of glucose and lipid metabolism. In this study, we investigated the association of plasma adipocytokine concentrations with markers of triglyceride-rich lipoprotein (TRL) metabolism in men. Methods: Fasting adiponectin, leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), apolipoprotein (apo) B-48, apo C-III, and remnant-like particle (RLP)-cholesterol concentrations were measured by immunoassays and insulin resistance by homeostasis assessment (HOMA) score in 41 nondiabetic men with a body mass index of 22–35 kg/m2. Visceral and subcutaneous adipose tissue masses (ATMs) were determined by magnetic resonance imaging and total ATM by bioelectrical impedance. Results: In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated with plasma apoB-48, apoC-III, RLP-cholesterol, triglycerides, VLDL-apoB, and VLDL-triglycerides (P <0.05). Resistin, IL-6, and TNF-α were not significantly associated with any of these variables, except for a direct correction between apoC-III and IL-6 (P <0.05). In multivariate regression including HOMA, age, nonesterified fatty acids, and adipose tissue compartment, adiponectin was an independent predictor of plasma apoB-48 (β coefficient = −0.354; P = 0.048), apoC-III (β coefficient = −0.406; P = 0.012), RLP-cholesterol (β coefficient = −0.377; P = 0.016), and triglycerides (β coefficient = −0.374; P = 0.013). By contrast, leptin was not an independent predictor of these TRL markers. Plasma apoB-48, apoC-III, RLP-cholesterol, and triglycerides were all significantly and positively associated with plasma insulin, HOMA, and visceral, subcutaneous, and total ATMs (P <0.05). Conclusions: These data suggest that the plasma adiponectin concentration may not only link abdominal fat, insulin resistance, and dyslipidemia, but may also exert an independent role in regulating TRL metabolism.

Download Full-text

Lower plasma adiponectin is a marker of increased intima-media thickness associated with type 2 diabetes mellitus and with male gender

Acta Endocrinologica ◽

10.1530/eje-06-0681 ◽

2007 ◽

Vol 156 (3) ◽

pp. 387-394 ◽

Cited By ~ 43

Author(s):

Robin P F Dullaart ◽

Rindert de Vries ◽

Arie van Tol ◽

Wim J Sluiter

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Intima Media Thickness ◽

Male Gender ◽

Diabetic Patients ◽

Lower Plasma ◽

Plasma Adiponectin ◽

Tnf Α

Objective: We tested the extent to which altered plasma adipokine levels may contribute to the increased carotid artery intima-media thickness (IMT) associated with type 2 diabetes mellitus and with male gender, independently of conventional cardiovascular risk factors, insulin resistance, and plasma C-reactive protein (CRP). Design: IMT (mean of three segments of both carotid arteries by ultrasonography), insulin resistance (homeostasis model assessment; HOMAir), plasma CRP, lipids, adiponectin, leptin, resistin, and tumor necrosis factor-α (TNF-α) were measured in 84 type 2 diabetic patients and 85 control subjects. Results: In diabetic patients, IMT (P<0.001), mean arterial pressure (P<0.001), HOMAir (P<0.001), plasma CRP (P=0.003), triglycerides (P=0.037), leptin (P=0.023), resistin (P=0.003), and TNF-α (P=0.003) levels were higher, whereas high-density lipoproteins (HDL) cholesterol (P<0.001) and adiponectin (P<0.001) levels were lower compared with control subjects. Plasma adiponectin (P<0.001) and leptin (P<0.001) were substantially lower in men than in women. IMT was positively and independently associated with age (P<0.001), diabetes (P=0.049), and male gender (P=0.002) in a multivariate regression model, not including other variables. Further analyses showed that IMT was positively related to age (P<0.001) and plasma triglycerides (P=0.038) and negatively to adiponectin (P<0.001), without independent effects of diabetes, gender, and HOMAir. Conclusions: Increased IMT in type 2 diabetes may in part be explained by lower plasma adiponectin and higher triglycerides, but not by leptin, resistin, and TNF-α. The gender effect on IMT is related to lower plasma adiponectin.

Download Full-text

A PPAR agonist improves TNF-α-induced insulin resistance of adipose tissue in mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2003.07.007 ◽

2003 ◽

Vol 309 (2) ◽

pp. 419-424 ◽

Cited By ~ 23

Author(s):

M Shibasaki ◽

K Takahashi ◽

T Itou ◽

H Bujo ◽

Y Saito

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Ppar Agonist ◽

Tnf Α

Download Full-text

TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00589.2012 ◽

2013 ◽

Vol 305 (1) ◽

pp. E101-E112 ◽

Cited By ~ 18

Author(s):

Ana Vázquez-Carballo ◽

Victòria Ceperuelo-Mallafré ◽

Matilde R. Chacón ◽

Elsa Maymó-Masip ◽

Margarita Lorenzo ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Signaling ◽

Visceral Fat ◽

Molecular Mechanisms ◽

Physiological Role ◽

Metabolic Effects ◽

Human Adipocytes ◽

Fat Depots ◽

Tnf Α

Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane-associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-α-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-α-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-α such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF-α, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-α on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK-induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF-α signaling by sTWEAK.

Download Full-text

Increased Subcutaneous and Epicardial Adipose Tissue Production of Proinflammatory Cytokines in Cardiac Surgery Patients: Possible Role in Postoperative Insulin Resistance

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-1044 ◽

2006 ◽

Vol 91 (11) ◽

pp. 4620-4627 ◽

Cited By ~ 158

Author(s):

Jaromir Kremen ◽

Marketa Dolinkova ◽

Jana Krajickova ◽

Jan Blaha ◽

Katerina Anderlova ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Cardiac Surgery ◽

Mrna Expression ◽

Proinflammatory Cytokines ◽

Epicardial Adipose Tissue ◽

Monocyte Chemoattractant Protein 1 ◽

Elective Cardiac Surgery ◽

Tnf Α ◽

History Of

Abstract Context: Hyperglycemia and insulin resistance frequently occur in critically ill patients even without a history of diabetes. Objective: Our objective was to study the role of adipose tissue hormonal production in the development of insulin resistance in cardiac surgery patients. Participants, Interventions, and Settings: Fifteen patients with elective cardiac surgery underwent blood sampling before, at the end, and 6, 12, 24, 48, and 120 h after the end of their operation. Epicardial and sc adipose tissue sampling was done at the beginning and at the end of surgery in the Department of Cardiac Surgery. Main Outcome Measures: We measured serum concentrations and sc and epicardial adipose tissue mRNA expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), TNF-α, leptin, resistin, and adiponectin and sc and epicardial adipose tissue mRNA expression of CD14, CD45, and CD68. Results: The rate of insulin infusion required to maintain euglycemia increased up to 7-fold 12 h after the operation, suggesting the development of insulin resistance. Serum IL-6 levels increased 43-fold 12 h after surgery. MCP-1 peaked 6-fold at the end of surgery. Smaller peaks of TNF-α and leptin appeared 6 and 12 h after surgery, respectively. Resistin levels peaked 4-fold 24 h after surgery, but adiponectin levels were not significantly affected. TNF-α and CD45 mRNA expression increased markedly during the operation in sc adipose tissue. IL-6, resistin, and MCP-1 mRNA expression increased in both sc and epicardial adipose tissue. Leptin, adiponectin, CD14, and CD68 mRNA expression did not change significantly. Conclusions: Both sc and epicardial adipose tissue is a source of proinflammatory cytokines in cardiac surgery patients and may contribute to the development of postoperative insulin resistance.

Download Full-text

A Fish Oil Diet Does Not Reverse Insulin Resistance despite Decreased Adipose Tissue TNF-α Protein Concentration in ApoE-3*Leiden Mice

Journal of Nutrition ◽

10.1093/jn/133.11.3350 ◽

2003 ◽

Vol 133 (11) ◽

pp. 3350-3355 ◽

Cited By ~ 20

Author(s):

Martin Muurling ◽

Ronald P. Mensink ◽

Hanno Pijl ◽

Johannes A. Romijn ◽

Louis M. Havekes ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Fish Oil ◽

Protein Concentration ◽

Tnf Α ◽

Fish Oil Diet

Download Full-text

Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00110.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. E527-E533 ◽

Cited By ~ 438

Author(s):

Jens M. Bruun ◽

Aina S. Lihn ◽

Camilla Verdich ◽

Steen B. Pedersen ◽

Søren Toubro ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Mrna Levels ◽

Plasma Adiponectin ◽

Tnf Α ◽

Adiponectin Mrna ◽

Before And After

Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-α). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-α on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% ( P < 0.05) increase in plasma adiponectin and a 45% ( P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% ( P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-α ( P < 0.01) and IL-6 plus its soluble receptor ( P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis.

Download Full-text

Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes

Diabetologia ◽

10.1007/s00125-007-0834-6 ◽

2007 ◽

Vol 50 (12) ◽

pp. 2562-2571 ◽

Cited By ~ 95

Author(s):

P. Plomgaard ◽

A. R. Nielsen ◽

C. P. Fischer ◽

O. H. Mortensen ◽

C. Broholm ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Tnf Α

Download Full-text

Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00184.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. E625-E632 ◽

Cited By ~ 46

Author(s):

Jennifer H. Lee ◽

John W. Bullen ◽

Violeta L. Stoyneva ◽

Christos S. Mantzoros

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Mrna Expression ◽

Mouse Models ◽

Uncoupling Protein ◽

High Fat ◽

Resistant Mouse ◽

Brown Adipose ◽

Tnf Α ◽

Resistin Mrna

Resistin is an adipocyte-secreted hormone proposed to link obesity with insulin resistance and diabetes, but no previous study has performed a joint quantitative evaluation of white adipose tissue (WAT) resistin mRNA expression and serum levels in relation to insulinemia and glycemia in mice. We have thus comparatively assessed WAT resistin mRNA expression and serum resistin levels in lean C57BL/6J mice and various mouse models of obesity, including diet-induced obese (DIO) C57BL/6J mice, high fat-fed TNF-α−/− mice, and brown adipose tissue (BAT)-deficient uncoupling protein-diphtheria toxin A chain (UCP1-DTA) mice. We also studied whether treatment with the weight-reducing and insulin-sensitizing compounds, MTII, an α-melanocyte-stimulating hormone analog, or CNTFAx15, a ciliary neurotrophic factor analog, alters resistin mRNA expression and/or circulating levels in lean and DIO C57BL/6J mice. We find that resistin mRNA expression is similar in DIO and lean C57BL/6J mice, as well as in TNF-α−/− and wild-type (WT) mice. Circulating resistin levels, however, are higher in DIO C57BL/6J, high fat-fed TNF-α−/−, and UCP1-DTA mice compared with lean controls. Moreover, although resistin mRNA expression is upregulated by MTII treatment for 24 h and downregulated by CNTFAx15 treatment for 3 or 7 days, circulating resistin levels are not altered by MTII or CNTFAx15 treatment. In addition, serum resistin levels, but not resistin mRNA expression levels, are correlated with body weight, and neither resistin mRNA expression nor serum resistin levels are correlated with serum insulin or glucose levels. We conclude that transcriptional regulation of resistin in WAT does not correlate with circulating resistin levels and that circulating resistin is unlikely to play a major endocrine role in insulin resistance or glycemia in mice.

Download Full-text

Brown Fat Lipoatrophy and Increased Visceral Adiposity through a Concerted Adipocytokines Overexpression Induces Vascular Insulin Resistance and Dysfunction

Endocrinology ◽

10.1210/en.2011-1765 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1242-1255 ◽

Cited By ~ 23

Author(s):

Almudena Gómez-Hernández ◽

Yolanda F. Otero ◽

Natalia de las Heras ◽

Óscar Escribano ◽

Victoria Cachofeiro ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Vascular Dysfunction ◽

Nuclear Factor Κb ◽

Brown Fat ◽

Visceral Adiposity ◽

Inflammatory Activity ◽

Nuclear Factor ◽

Antibody Treatment ◽

Tnf Α

In this study, we analyzed the role played by concerted expression of adipocytokines associated with brown fat lipoatrophy and increased visceral adiposity on triggering vascular insulin resistance and dysfunction in brown adipose tissue (BAT) insulin receptor knockout (BATIRKO) mice. In addition, we assessed whether vascular insulin resistance may aggravate vascular damage. The 52-wk-old, but not 33-wk-old, BATIRKO mice had a significant decrease of BAT mass associated with a significant increase of visceral white adipose tissue (WAT) mass, without changes in body weight. Brown fat lipoatrophy and increased visceral adiposity enhanced the concerted expression of adipocytokines (TNF-α, leptin, and plasminogen activator inhibitor 1) and nuclear factor-κB binding activity in BAT and visceral WAT, mainly in the gonadal depot, and aorta. Although those mice showed insulin sensitivity in the liver and skeletal muscle, insulin signaling in WAT (gonadal depot) and aorta was markedly impaired. Treatment with anti-TNF-α antibody impaired the inflammatory activity in visceral adipose tissue, attenuated insulin resistance in WAT and aorta and induced glucose tolerance. Finally, 52-wk-old BATIRKO mice showed vascular dysfunction, macrophage infiltration, oxidative stress, and a significant increase of gene markers of endothelial activation and inflammation, the latter effect being totally reverted by anti-TNF-α antibody treatment. Our results suggest that brown fat lipoatrophy and increased visceral adiposity through the concerted overexpression of cytoadipokines induces nuclear factor-κB-mediated inflammatory signaling, vascular insulin resistance, and vascular dysfunction. Inhibition of inflammatory activity by anti-TNF-α antibody treatment attenuates vascular insulin resistance and impairs gene expression of vascular dysfunction markers.

Download Full-text

Role of adipokines and nonesterified fatty acids in the development of insulin resistance

Problems of Endocrinology ◽

10.14341/probl200955313-16 ◽

2009 ◽

Vol 55 (3) ◽

pp. 13-16 ◽

Cited By ~ 1

Author(s):

D. A. Tanyanskiy ◽

E M. Firova ◽

L. V. Shatilina ◽

A. D. Denisenko

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Body Weight ◽

Adipose Tissue ◽

Regression Analysis ◽

Linear Regression Analysis ◽

Biologically Active ◽

Homa Index ◽

Nonesterified Fatty Acids

The purpose of the study was to reveal a possible role of adipokines, biologically active adipose tissue proteins (leptin and adiponectin) and nonesterified fatty acids in generating insulin resistance (IR). One hundred and fifty-seven patients (90 females and 67 males) aged 57.5±9.2 years were enrolled in the study. According to the HOMA index for IR, the patients were divided into 3 equal groups. The examinees with a high HOMA index were found to have elevated levels of fatty acids, leptin and decreased concentrations of adiponectin. At the same time according to the linear regression analysis, all these indices are its independent determinants. However, analysis of the data in the groups of patients with different body weight revealed that the increased concentrations of fatty acids and leptin may play a role in the development of IR in subjects with obesity while the higher level of fatty acids and lower adiponectin may be involved in patients without noticeable obesity. Thus, it may be assumed that leptin, adiponectin and nonesterified fatty acids may affect the development of IR; however, their contribution depends on the degree of adiposity.

Download Full-text