Diet-Induced Obesity: EPO Has Anti-Inflammatory Effect on White Adipose Tissue

MedicalResearch.com Interview witih:
Dr. Constance Tom Noguchi, Ph.D.
Molecular Medicine Branch
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892  and

Dr. Mawadda Al-Naeeli
Department of Biological Sciences, Ohio University

MedicalResearch.com: What are the main findings of the study?

Answer: The main findings of our study are:
1) EPO treatment has an anti-inflammatory effect on white adipose tissue macrophage population during diet-induced obesity in addition to its associated metabolic improvements on glucose tolerance and insulin sensitivity in vivo.
2) In this model of obesity, EPO treatment was found to reduce M1-like [pro-inflammatory] and increased M2-like [anti-inflammatory] macrophages in visceral white adipose tissue depot.
3) In addition, EPO decreased circulating inflammatory monocytes.
4) These anti-inflammatory effects of EPO were found to be driven, at least in part, by direct EPO-R response in macrophages via Stat3 activation, where EPO effects on M2 but not M1 macrophages required interleukin-4 receptor/Stat6 axis.
5) The anti-inflammatory effects of EPO are not restricted to treatment with exogenous high dose EPO (1000U/kg), but also include endogenous physiological EPO levels as demonstrated by the series of studies conducted using ΔEpoR mice with EPO-R restricted to erythroid cells.

MedicalResearch.com: Were any of the findings unexpected?

Answer: Yes. The most unexpected findings were

1) The observation that EPO promotes the expansion of the white adipose tissue M2-like macrophage population, as a result of increased IL-4 levels that drive their proliferation in situ.

2) the anti-inflammatory effects of EPO emerging prior to any
detectable changes in body weight or composition, and

3) the absence of metabolic effects for EPO on glucose uptake locally in the white adipose tissue, despite high levels of EPO-R expression.

MedicalResearch.com: What should clinicians and patients take away from your report?

Answer: The main message from our report is that EPO/EPO-R signaling regulates inflammation in the white adipose tissue during obesity. We know based on previous reports that EPO can inhibit macrophage inflammatory response in the gut and systemically as published by Nairz et al Immunity 2011.

Our findings further emphasize and extend the nonerythroid activity of EPO to encompass effects on both macrophage infiltration and subset composition,at least in fat, with potential implications in clinical practice. If EPO has anti-inflammatory effects in humans, and can expand anti-inflammatory macrophage population in vivo, the potential contribution of EPO stimulated macrophage response to improve insulin sensitivity warrants further investigation. In addition, the contribution of EPO stimulated macrophage response may also relate to the increase tumor growth reported in some cancer patients receiving high dose EPO therapy to treat anemia, especially in light of the strong correlation between tumor infiltrating macrophages and poor prognosis.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Answer: Existing reports in the literature already show that EPO has the potential to regulate human immune responses especially in renal dialysis patients and in multiple myeloma patients. The recommendation for future research is translational studies to investigate the effect for clinically relevant EPO doses on inflammatory and immune response effector cells/functions in humans to shed light on the biology involved during health and disease.

Citation:

Erythropoietin signaling: A novel regulator of white adipose tissue inflammation during diet-induced obesity

Mawadda Alnaeeli, Bruce M Raaka, Oksana Gavrilova, Ruifeng Teng, Tatyana Chanturiya, and Constance Tom Noguchi

Diabetes published ahead of print March 19, 2014, doi:10.2337/db13-0883 1939-327X