Highlights
- •Increased secretion of Fetuin A and LBP from adipose tissue of MetS subjects, which correlates with insulin resistance.
- •The study documents increased secretion of DAMP, HMGB1 and increased TLR2 and TLR4 protein in subcutaneous adipose.
- •We demonstrate increased mRNA for Fetuin A, LBP and HMGB1 in mice fat depots and adipocytes.
Abstract
Objective
Adipose Tissue (AT) dysregulation contributes to the pro-inflammatory state and insulin
resistance of Metabolic Syndrome (MetS). We examined AT secretion of the hepatokine,
Fetuin-A, LBP, sCD14 and HMGB-1, and toll-like receptor 2 and 4 protein levels in
MetS and controls.
Design and methods
Secreted levels of Fetuin-A, LBP, HMGB-1 and sCD14 and TLR2 and TLR4 protein in AT
of controls and MetS patients were assayed. Also mRNA and protein for Fetuin-A, LBP,
sCD14 and HMGB-1 were studied in subcutaneous fat depot of mice and during adipocyte
differentiation.
Results
Secretion of Fetuin-A, LBP and HMGB-1 from AT were significantly increased in MetS
(n = 28) compared to controls (n = 25), even after adjustment for adiposity. There
were no significant differences in sCD14. Both LBP and Fetuin-A correlated significantly
with HOMA-IR and increased significantly with increasing features of MetS. There was
a significant increase in AT TLR2 and TLR4 protein in MetS compared to controls. Expression
of Fetuin-A and LBP were significantly higher in subcutaneous white adipose tissue of HFD fed mice as
well as in ob/ob mice compared to C57BL6/J control mice (n = 6 per group). Additionally
mRNA and protein levels of FetA, LBP and HMGB-1 increased during differentiation of 3T3-L1 adipocytes.
Conclusions
We make the novel observation of increased secretion of Fetuin A, LBP and HMGB-1 from
AT and hypothesize that these engage TLRs in AT and other tissues contributing to
the pro-inflammatory state and insulin resistance of MetS.
Keywords
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References
- Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: executive summary.Circulation. 2005; 112: 2735-2752
- International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645
- Increased toll-like receptor activity in patients with metabolic syndrome.Diabetes Care. 2012; 35: 900-904
- Increased Toll-like receptor (TLR) mRNA expression in monocytes is a feature of metabolic syndrome in adolescents.Pediatr. Obes. 2013; 8: e19-23
- Toll-like receptor status in obesity and metabolic syndrome: a translational perspective.J. Clin. Endocrinol. Metab. 2014; 99: 39-48
- Adipose tissue dysregulation in patients with metabolic syndrome.J. Clin. Endocrinol. Metab. 2011; 96 (7): E1782-E1788
- Adipose tissue dysfunction in nascent metabolic syndrome.J. Obes. 2013; 2013: 393192
- Increased chemerin and decreased omentin-1 in both adipose tissue and plasma in nascent metabolic syndrome.J. Clin. Endocrinol. Metab. 2013; 98: E514-E517
- The role of hepatokines in metabolism.Nat. Rev. Endocrinol. 2013; 9: 144-152
- Fetuin-A: the missing link in lipid-induced inflammation.Nat. Med. 2012; 18: 1182-1183
- Old and new findings on lipopolysaccharide-binding protein: a soluble pattern-recognition molecule.Biochem. Soc. Trans. 2011; 39: 989-993
- Health aging and body composition study. Fetuin-A and change in body composition in older persons.J. Clin. Endocrinol. Metab. 2009; 94: 4492-4498
- Adipokine pattern in subjects with impaired fasting glucose and impaired glucose tolerance in comparison to normal glucose tolerance and diabetes.PLoS One. 2010; 5 (9): e13911
- Fetuin-A: a novel link between obesity and related complications.Int. J. Obes. (Lond). 2014; ([Epub ahead of print])https://doi.org/10.1038/ijo.2014.203
- Hepatocytes contribute to soluble CD14 production, and CD14 expression is differentially regulated in hepatocytes and monocytes.J. Biol. Chem. 2000; 275: 36430-36435
- High-mobility group box family of proteins: ligand and sensor for innate immunity.Trends Immunol. 2012; 33: 633-640
- HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease.Nat. Rev. Rheumatol. 2012; 8: 195-202
- Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin.Annu Rev. Immunol. 1995; 13: 437-457
- Accessory molecules for Toll-like receptors and their function.Nat. Rev. Immunol. 2012; 12: 168-179
- Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.Nat. Med. 2012; 18: 1279-1285
- Increased cellular and circulating biomarkers of oxidative stress in nascent metabolic syndrome.J. Clin. Endocrinol. Metab. 2012; 97: E1844-E1850
- Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk.Atherosclerosis. 2010; 211: 297-302
- Circulating pathogen associated molecular pattern – binding proteins and high mobility group box protein 1 in nascent metabolic syndrome: implications for cellular Toll-like receptor activity.Atherosclerosis. 2014; 236: 182-187
- Regulation of the SNARE-interacting protein Munc18c tyrosine phosphorylation in adipocytes by protein-tyrosine phosphatase 1B.Cell. Commun. Signal. 2013; 11: 57-64
- A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese.Diabetes Care. 2010; 33 (24Pubmed): 1925-1932
- A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction.Diabetologia. 2013; 56 (25): 2524-2537
- Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria.Biochem. Soc. Trans. 2003; 31 (26): 785-790
- MicroRNAs regulated by adiponectin as novel targets for controlling adipose tissue inflammation.Endocrinology. 2012; 153: 5285-5296
- Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans.Diabetes Care. 2006; 29 (28): 853-857
- Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans.Nat. Med. 2013; 19 (29): 394-395
- Association between human Fetuin-A and the metabolic syndrome: data from the Heart and Soul Study.Circulation. 2006; 113: 1760-1767
Xu Y, Xu M, Bi Y, Song A, Huang Y, Liu Y, Wu Y, Chen Y, Wang W, Li X, Ning G. Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese. Atherosclerosis. double citation.
- Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages.J. Biol. Chem. 2013; 288: 28324-28330
- Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein.J. Biol. Chem. 2004; 279: 7370-7377
- Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in β-cells.Int. J. Obes. (Lond). 2014 Feb 28; https://doi.org/10.1038/ijo.2014
- Inflammation triggers high mobility group box 1 (HMGB1) secretion in adipose tissue, a potential link to obesity.Cytokine. 2013; 64: 103-111
- Fetuin-A: a novel link between obesity and related complications.Int. J. Obes. (Lond). 2014 Dec 3; ([Epub ahead of print])https://doi.org/10.1038/ijo.2014.203
- Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance.Int. J. Obes. (Lond). 2012; 36: 1442-1449
- Bariatric surgery decreased the serum level of an endotoxin-associated marker: lipopolysaccharide-binding protein.Surg. Obes. Relat. Dis. 2014; 10: 1182-1187
- Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial.J. Acquir Immune Defic. Syndr. 2015; 68: 256-263
- Effect of simvastatin or its combination with ezetimibe on Toll-like receptor expression and lipopolysaccharide – induced cytokine production in monocytes of hypercholesterolemic patients.Atherosclerosis. 2012; 225: 381-387
Article info
Publication history
Published online: April 30, 2015
Accepted:
April 24,
2015
Received in revised form:
April 24,
2015
Received:
February 20,
2015
Identification
Copyright
Published by Elsevier Inc.