Macrophages From Visceral Adipose Tissue Contribute To The Onset Of Diabetes
Melanie Rodrigues, PhD, Michael W. Findlay, PhD, FRACS, Nathaniel Fernhoff, PhD, Alexander J. Whittam, BS, Michael Sorkin, MD, Michael Januszyk, MD PhD, Revanth Kosaraju, High School, Robert C. Rennert, MD, Peter A. Than, MD, Geoffrey C. Gurtner, MD.
Stanford, Stanford, CA, USA.
PURPOSE: Obesity is characterized by increased visceral adipose tissue (VAT) and is the primary risk factor for type2 diabetes. Both obesity and diabetes are now recognized as chronic pro-inflammatory diseases with the accumulation of macrophages. However, the cellular and molecular mechanisms that underlie the increase in VAT macrophages, and contribution of these macrophages to diabetes remain unclear.
METHODS: We used fluorescent assisted cell sorting to isolate CD45+CD11b+F480+ macrophages from the VAT of normal, obese and high fat diet (HFD)-induced diabetic mice. CD45+CD11b+CD66b- macrophages from human subcutaneous adipose tissue and VAT from normal, obese and diabetic patients were similarly isolated. Single cell transcriptional analysis and RNA sequencing were used to determine polarization within the macrophages without prior surface marker bias. To identify the contribution of macrophages to diabetes, VAT macrophages were isolated from diabetic and normal mice, and injected into the VAT of normal mice. Finally, to test for reversal of diabetes, VAT was surgically resected from diabetic mice, and the mice placed on HFD or regular chow.
RESULTS: We observe an increase in bone marrow derived pro-inflammatory VAT macrophages releasing IL6, IL1b and TNF with the onset of diabetes. Normal mice injected with these pro-inflammatory macrophages, in the presence of HFD develop diabetes significantly faster. Resection of VAT from HFD-induced diabetic mice in the presence of normal chow significantly quickens reversal of diabetes.
CONCLUSION: Our results suggest that pro-inflammatory bone marrow derived macrophages in the VAT contribute to diabetes. Directed intervention of these cells will have implications in treating diabetes.
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