Aberrant activation of bone marrow Ly6Chighmonocytes in diabetic mice contributes to impaired glucose tolerance.

Yosuke Ikeda,Shinichiro Kimura,Noriyuki Sonoda,Battsetseg Bachuluun,Toyoshi Inoguchi,Yoshihiro Ogawa,Nikolaos Frangogiannis

doi:10.1371/journal.pone.0229401

Yosuke Ikeda, Shinichiro Kimura + Show 5 more

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https://doi.org/10.1371/journal.pone.0229401

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Abstract

Accumulating evidence indicates that diabetes and obesity are associated with chronic low-grade inflammation and multiple organ failure. Tissue-infiltrated inflammatory M1 macrophages are aberrantly activated in these conditions and contribute to hyperglycemia and insulin resistance. However, it is unclear at which stage these cells become aberrantly activated: as precursor monocytes in the bone marrow or as differentiated macrophages in tissues. We examined the abundance, activation state, and function of bone marrow-derived Ly6Chigh monocytes in mice with diabetes and/or obesity. Ly6Chigh monocytes were FACS-purified from six groups of male mice consisting of type 2 diabetes model db/db mice, streptozotocin (STZ) induced insulin depletion mice, high fat diet (HFD) induced obesity mice and each control mice. Ly6Chigh monocytes were then analyzed for the expression of inflammation markers by qRT-PCR. In addition, bone marrow-derived Ly6Chigh monocytes from db/+ and db/db mice were fluorescently labeled and injected into groups of db/db recipient mice. Cell trafficking to tissues and levels of markers were examined in the recipient mice. The expression of many inflammation-related genes was significantly increased in Ly6Chigh monocytes from db/db mice, compared with the control. Bone marrow-derived Ly6Chigh monocytes isolated from db/db mice, but not from db/+ mice, displayed prominent infiltration into peripheral tissues at 1 week after transfer into db/db mice. The recipients of db/db Ly6Chigh monocytes also exhibited significantly increased serum glucose levels and worsening tolerance compared with mice receiving db/+ Ly6Chigh monocytes. These novel observations suggest that activated Ly6Chigh monocytes may contribute to the glucose intolerance observed in diabetes.

Highlights

Chronic low-grade inflammation is an important contributor to multiple organ failure in patients with diabetes and obesity [1, 2]
To assess the development of diabetes in each of the three mouse models studied here, we examined the body weights and blood glucose levels of 8-week-old db/db, db/+ mice, C57BL/6 mice administered STZ or vehicle, and C57BL/6 mice fed control diet (CD) or a high fat diet (HFD) until they were 16 weeks of age (Figs 1 and 2)
We investigated the potential contribution of aberrantly activated Ly6Chigh monocytes to the development and phenotype of diabetic and obese mice

Summary

Introduction

Chronic low-grade inflammation is an important contributor to multiple organ failure in patients with diabetes and obesity [1, 2]. The prevalence of metabolic syndrome including obesity and diabetes continues to increase. We have previously reported that inflammatory and oxidative stress mediators, including reactive oxygen species produced via protein kinase C (PKC)-dependent activation of NAD(P)H oxidase, contributes to the development of atherosclerotic complications in patients with diabetes and metabolic syndrome [3, 4]. Inflammatory M1 macrophages are thought to play important roles in diabetes and obesity through infiltration into adipose tissue and production of reactive oxygen species and inflammatory mediators, which cause chronic local inflammation [5, 6] and dysregulation of adipocytokines [7]. The extent to which bone marrow-derived monocytes may contribute to the chronic inflammation observed in obesity and diabetes remains unclear. Pro-inflammatory (CD14 + CD16+) monocytes are more abundant in the peripheral blood of patients with type 2 diabetes compared with normal subjects [8], suggesting that this may be the case

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