Objective: Adipose tissue inflammation induced by macrophage infiltration through the C-C motif chemokine receptor (CCR) 2 or CCR5 pathway has a pivotal role in obesity-related disease and insulin resistance. Here, the effect of PF4178903, a dual CCR2/CCR5 antagonist, on obesity and insulin resistance was evaluated. Methods: Forty male C57BL/6J mice were divided into four groups as follows: (1) regular diet (RD), (2) RD with PF4178903, (3) high-fat diet (HFD), and (4) HFD with PF4178903. All mice were sacrificed 12 weeks after the beginning of the experiment. Biochemical analyses and adipose tissue examinations were performed. Results: After treatment with PF4178903, both body weight and adipocyte size in white adipose tissue were decreased in HFD-fed mice. Furthermore, PF4178903 treatment reduced adipose tissue macrophages (ATMs) and lowered serum proinflammatory cytokines in HFD-fed mice. PF4178903 treatment significantly improved HFD-induced insulin resistance and glucose intolerance. Fluorescence-activated cell sorter analysis revealed that PF4178903 treatment reduced the CD8 + T cell fraction in white adipose tissue of HFD-fed mice. PF4178903 treatment reduced M1-polarized macrophages while inducing an M2-dominant shift in macrophages within white adipose tissue in HFD-fed mice. Conclusions: Dual CCR2/CCR5 antagonism ameliorates insulin resistance and inflammation in obesity by regulating ATM recruitment and polarization in white adipose tissue.
Bibliographical noteFunding Information:
Funding agencies: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (NRF-2016R1A6A3A11932829). PF4178903 received research support from Pfizer. Disclosure: The authors declared no conflict of interest. Author contributions: HMK and JHH conducted the experiments and data analysis and wrote the manuscript. ESL, BRL, and MHK conducted the experiments and data analysis. JHH, BRL, and HJK contributed to the development of analytical tools and discussion. HMK, HJK, and JHH contributed to the experimental design and discussion. CHC contributed to the experimental design and wrote the manuscript. *Ji Hye Huh and Hong Min Kim contributed equally to this work. Additional Supporting Information may be found in the online version of this article. Received: 30 August 2017; Accepted: 26 November 2017; Published online 27 December 2017. doi:10.1002/oby.22103
All Science Journal Classification (ASJC) codes
- Medicine (miscellaneous)
- Endocrinology, Diabetes and Metabolism
- Nutrition and Dietetics