To the Editor: We read with interest the research letter entitled ‘Plasma fetuin-A does not correlate with monocyte TLR4 in humans’ by Jialal and colleagues [1]. The authors state that: ‘Studies using animal models, largely the work of Pal et al [2], have elegantly demonstrated that fetuin-A is the endogenous ligand for Toll-like receptor 4 (TLR4) via which lipids such as fatty acids induce insulin resistance, but there are no data in support of this in humans’. This is not, in fact, the case: in the paper referred to [2], our group provided data on human adipocytes from both diabetic and non-diabetic participants showing that fetuin-A acts as an endogenous ligand of TLR4 to induce insulin resistance. In another recent review, Stefan and Häring observed a significant correlation between circulating fetuin A and insulin resistance in humans [3].
Jialal et al also state: ‘Based on our findings, we propose that until larger studies report significant correlations between TLR4 expression in monocytes/adipose tissue and circulating fetuin-A in humans with obesity, the metabolic syndrome or diabetes, the relationship between these two proteins demonstrated in animals might not translate to humans’. In our Nature Medicine paper [2], we have clearly shown a significant correlation between plasma fetuin-A and TLR4 expression in adipocytes from abdominal subcutaneous adipose tissue of obese human subjects with type 2 diabetes.
We have shown that circulating NEFA stimulates the production of fetuin-A by the liver via NF-κB. Fetuin-A then forms a dimer with NEFA by acting as its binding protein. The NEFA–fetuin-A dimer finally binds to TLR-4 present on the surface of adipocytes and macrophages, resulting in the formation of a ternary complex that triggers a local inflammatory response in the adipose tissue. Upon stimulation by circulating fetuin-A, white adipose tissue attracts circulating M2 macrophages that undergo proinflammatory polarisation to M1 under the influence of fetuin-A generated locally by the inflamed adipocytes [4, 5]. Jialal et al drew conclusions based on their studies on circulating monocytes, which are not the most appropriate model to study the NEFA–fetuin-A–TLR4 relationship [1]. Such interactions have only been reported to take place in the adipose tissue, not only by our group but also by others. In a recent paper, Trepanowski et al proposed a model wherein they suggest that: ‘Fetuin-A originating from hepatocytes and adipocytes sends chemoattractant signals that induce macrophage infiltration into adipose tissue and subsequent conversion to a classically activated M1 subtype. Fetuin-A then presents fatty acids to the TLR4 receptors on both M1 macrophages and adipocytes, thereby propagating the release of proinflammatory cytokines’ [6]. Moreover, our hypothesis concerned TLR4 activation and NOT expression, which Jialal et al went on to study [1]. Finally, their concluding remarks on fetuin-A and TLR4 expression in monocytes/adipose tissue goes against the existing literature on the subject and unnecessarily creates a lot of confusion.
Abbreviations
- TLR4:
-
Toll-like receptor 4
References
Jialal I, Devaraj S, Adams-Huet B (2016) Plasma fetuin-A does not correlate with monocyte TLR4 in humans. Diabetologia 59:222–223
Pal D, Dasgupta S, Kundu R et al (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285
Stefan N, Häring H-U (2013) The role of hepatokines in metabolism. Nat Rev Endocrinol 9:144–152
Chatterjee P, Seal S, Mukherjee S et al (2013) Adipocyte fetuin A contributes to macrophage migration in adipose tissue and polarization of macrophages. J Biol Chem 288:28324–28330
Mukhopadhyay S, Mondal S, Kumar M, Dutta D (2014) Proinflammatory and antiinflammatory attributes of fetuin-A: a novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome. Endocr Pract 20:1345–1351
Trepanowski JF, Mey J, Varady KA (2015) Fetuin-A: a novel link between obesity and related complications. Int J Obes 39:734–741
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Mukhopadhyay, S., Bhattacharya, S. Plasma fetuin-A triggers inflammatory changes in macrophages and adipocytes by acting as an adaptor protein between NEFA and TLR-4. Diabetologia 59, 859–860 (2016). https://doi.org/10.1007/s00125-016-3866-y
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DOI: https://doi.org/10.1007/s00125-016-3866-y