Referee 1's Review (Antonio Vidal-Puig):

The manuscript has been improved particularly with the in vitro experiments demonstrating that fetuin acts in adipocytes in vitro.

However I think there still a few things that are fundamental to make the main claim of the paper: " that fetuin A is a liver originated molecule that acts on the adipose tissue to induce a more proinflammatory profile" .. I think the in vitro experiments are convincing and I am convinced that fetuin can act in the adipose tissue. However I would like to see data and/or published references showing: a) that in adipose tissue from obese insulin resistant individuals and/or animals fetui A expression is not induced de novo in adipose tissue. This is important because the fact that a healthy adipose tissue may not express fetuin does not prevent that fetuin could not be induced in adipose tissue under pathological conditions leading to insulin resistance e.g obesity. I understand that the authors may not want to do more biosies but it should be easy to contact one of the multiple groups working in obesity and ask for some RNA from lean, obese and morbid obese individuals.

The other question that does not make too much sense is that fetuin A on one hand decreases adiponectin, PPArg, is associated with insulin resistance and according to published literature from 1990 promotes adipogenesis. This in my opinion would be very unexpected. I do not know how to reconcile this poradipogenic effect on the face ofthe proinflammatory effect.

Having said that I am more supportive ofthsi manuscript.the manuscript is more convincing now.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.