Effects of Obesity-Associated Chronic Inflammation on Peripheral Blood Immunophenotype Are Not Mediated by TNF in Female C57BL/6J Mice

Abstract

Chronic low-grade systemic inflammation in obesity contributes to the development and progression of aspects of metabolic syndrome. In obese male mice, expanded adipose tissue releases proinflammatory cytokines, including TNF, which promotes an increase in immature, proinflammatory, peripheral blood Ly-6C high monocytes. The aim of this study was to characterize how TNF alters circulating cellular immunity in female mice with diet-induced obesity. We initially quantified peripheral blood immune cells by flow cytometry in female wild-type C57BL/6J mice after 3-30 wk of allocation to a high-fat (HF) or standard chow diet. We assessed effects of diet and time on neutrophil, monocyte, B cell, NK cell, CD4 + T cell, and CD8 + T cell populations. There was a significant interaction of the effects of diet type and time on the numbers and prevalence of circulating total monocytes and Ly-6C high , Ly-6C low , and Ly-6C 2 subsets. Circulating monocytes, in particular Ly-6C high monocytes, were increased in HF-fed mice compared with chowfed mice. Ly-6C high monocytes from HF-fed mice also had a more immature phenotype yet were highly responsive to the chemotactic ligand CCL2 and had greater intracellular production of TNF. Comparisons of the effects of HF diet feeding in littermate wild-type (TNF +/+ ) and TNF 2/2 female mice showed that genetic ablation of TNF did not protect from higher adiposity or an increase in circulating, immature, proinflammatory Ly-6C high monocytes during HF diet-induced obesity. These data emphasize the importance of considering biological sex when determining the mechanisms of TNF action in obesity-induced cellular inflammation and in other chronic inflammatory conditions. ImmunoHorizons, 2021, 5: 370-383.

Intestinal permeability and peripheral immune cell composition are altered by pregnancy and adiposity at mid- and late-gestation in the mouse

“…7 i ; see Figure S3 for other immune cell counts). Circulating monocytes are derived from bone marrow precursors, and HF diet promotes bone marrow myelopoiesis and egress of Ly6C high monocytes into circulation in non-pregnant females (31). Assessment of bone marrow in HF-fed dams compared to CTL-fed dams at E14.5 likewise showed elevated total quantities of leukocytes (Fig.…”

“…We now also report significant modifications in blood immune cell composition in HF-fed dams at E14.5, but not E18.5. We have previously shown that non-pregnant female mice with diet-induced obesity have increased numbers of circulating TNF-producing inflammatory Ly6C high monocytes (31). Here we similarly show that Ly6C high monocytes were increased in HF-fed dams at mid-but not late gestation compared to CTL dams.…”

“…We have shown in non-pregnant female mice that diet-induced obesity results in tissue- and time-dependent physiological changes within the intestines, including shortening of ileum and colon lengths and elevated paracellular permeability (unpublished data). These changes are accompanied by alterations in peripheral metabolism, increased circulating inflammatory Ly6C high monocytes, and the accumulation of inflammatory macrophages in adipose tissue, contributing to metabolic dysregulation (31). Thus, maintenance of the intestinal barrier is essential to prevent both local and systemic effects of HF diet intake.…”

More Active Intestinal Immunity Developed by Obese Mice Than Non-Obese Mice After Challenged by Escherichia coli

“…Obesity has become a fast-growing global health problem in today's society, which can have a major negative impact on life. There is evidence that obesity affects the immune system (4)(5)(6), and an association between obesity and chronic inflammation has been demonstrated (7)(8)(9).…”

Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages in female mice independent of TNF

“…Changes to monocyte-derived macrophage phenotype and function may also occur within intestinal tissues under conditions of the systemic, low-grade and chronic inflammation that is characteristic of obesity (Hotamisligil, 2017). Obesity increases circulating Ly6C high monocytes (Breznik et al ., 2018; Breznik et al ., 2021a), which differentiate into pro-inflammatory macrophages within metabolic tissues like adipose (Weisberg et al ., 2003; Kanda et al ., 2006). While it has been reported that there is an accumulation of pro-inflammatory macrophages within the colon in obesity (Kawano et al ., 2016), which could contribute to observations of obesity-associated increases in gut permeability (Cani et al ., 2007; Cani et al ., 2008; Johnson et al ., 2015; Kawano et al ., 2016), there is a lack of consensus across published research (Garidou et al ., 2015; Johnson et al ., 2015; Hong et al ., 2017; Luck et al ., 2019; Rohm et al ., 2022).…”