@article{589196524aae436ea66b0bd084ba5df6,
title = "Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice",
abstract = "Diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD) are common diabetic complications with limited treatment options. Experimental studies show that targeting inflammation using chemokine receptor (CCR) antagonists ameliorates DKD, presumably by reducing macrophage accumulation or activation. As inflammation is implicated in DPN development, we assessed whether CCR2 and CCR5 antagonism could also benefit DPN. Five-week-old ob/ob mice were fed a diet containing MK-0812, a dual CCR2-CCR5 receptor antagonist, for 8 weeks; DPN, DKD and metabolic phenotyping were then performed to determine the effect of CCR inhibition. Although MK-0812 reduced macrophage accumulation in adipose tissue, the treatment had largely no effect on metabolic parameters, nerve function or kidney disease in ob/ob mice. These results conflict with published data that demonstrate a benefit of CCR antagonists for DKD and hyperglycaemia. We conclude that CCR signaling blockade is ineffective in ob/ob mice and suspect that this is explained by the severe hyperglycaemia found in this model. It remains to be determined whether MK-0812 treatment, alone or in combination with improved glycaemic control, is useful in preventing diabetic complications in alternate animal models.",
keywords = "animal pharmacology, diabetes complications, diabetic nephropathy, diabetic neuropathy, drug mechanism, mouse model",
author = "O'Brien, {Phillipe D.} and Hinder, {Lucy M.} and Parlee, {Sebastian D.} and Hayes, {John M.} and Carey Backus and Hongyu Zhang and Lijun Ma and Sakowski, {Stacey A.} and Brosius, {Frank C.} and Feldman, {Eva L.}",
note = "Funding Information: The authors acknowledge the technical expertise of Ms. Jacqueline Dauch, Ms. Chelsea Lindblad, Ms. Jharna Saha and Dr. Sang Su Oh in conducting animal experiments. The authors thank the Hormone Core at Vanderbilt University and the Lipid Laboratory at the Mouse Metabolic Phenotyping Center at the University of Washington for mouse plasma measurements, respectively, and the Chemistry Core of the MDRTC (930DK020572) at the U-M for %GHb measurements. The authors thank Dr. Charlie Alpers at the University of Washington for expert advice on the ob/ob mouse strain. L. M. is employed as an Associate Principal Scientist at Merck Pharmaceuticals, Kenilworth, New Jersey. No other potential conflicts of interest relevant to this article were reported. P. D. O. and L. M. H. directed the study, interpreted the data and wrote the manuscript. S. D. P. provided consultation, performed experimental work and contributed to the discussion of the manuscript. J. M. H, C. B. and H. Z. conducted animal experiments. L. M. was involved in study design, provided consultation and interpreted the pharmacokinetic data. S. A. S reviewed and edited the manuscript. E. L. F. and F. C. B. designed and directed the study, contributed to discussion and edited the manuscript. All authors critically revised the manuscript. E. L. F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Funding Information: Funding was provided by the National Institutes of Health (1DP3DK094292, 1R24082841 to E. L. F and F. C. B.); Novo Nordisk Foundation (NNF14SA0006 to E.L.F.), Juvenile Diabetes Research Foundation (Post-doctoral Fellowship to L. M. H.), Milstein, Nathan and Rose Research Fund; Sinai Medical Staff Foundation Neuroscience Scholar Fund 2; Robert C Graham Fund; Walbridge Aldinger Graduate Fellowship Fund (Post-doctoral Fellowship to P. D. O); American Diabetes Association; Program for Neurology Research and Discovery; A. Alfred Taubman Medical Research Institute; and the University of Michigan Center for Organogenesis Non-Traditional Post-Doctoral Fellowship (to S. D. P). Publisher Copyright: {\textcopyright} 2017 John Wiley & Sons Ltd",
year = "2017",
month = oct,
doi = "10.1111/dom.12950",
language = "English (US)",
volume = "19",
pages = "1468--1472",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "Wiley-Blackwell",
number = "10",
}