Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity

Abstract

The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.

Dysbiosis in imiquimod-induced psoriasis alters gut immunity and exacerbates colitis development

“…The increased colon length in IMQ-pso mice confirmed the increased fermentative activity of the microbiota commonly associated with succinate production (Armstrong et al, 2021). Increased microbiota-derived succinate has been reported in other non-communicable diseases such as IBD and associated comorbidities, including arthritis and calcium oxalate kidney stones (Fremder et al, 2021), as well as in obesity, a condition in which increased numbers of pro-inflammatory intestinal macrophages were reported (Rohm et al, 2021(Rohm et al, , 2022. While succinate can be used as a source of nutrients for intestinal pathogen Article ll OPEN ACCESS colonization or proliferation (Fernandez-Veledo and Vendrell, 2019;Fremder et al, 2021), it may also contribute to the stable colonization by pathobionts, perpetuating dysbiosis in psoriasis.…”

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

“…These effects could in addition be further modified by biological sex, which influences both immunity and metabolism (Tramunt et al ., 2020; Breznik et al ., 2021b). It has been reported that TNF-producing monocyte-derived colon macrophages contribute to obesity-associated metabolic dysfunction in male mice (Kawano et al ., 2016; Rohm et al ., 2022). However, we have observed that while both obese male and female mice have an increase in circulating inflammatory TNF-producing Ly6C high monocytes and adipose tissue macrophage accumulation, in female mice the metabolic dysregulation is attenuated, and these changes are not dependent on TNF (Breznik et al ., 2018; Breznik et al ., 2021b).…”

“…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). This is likely due to differences in the methods and tissue regions of assessment, length of diet allocation, and selection of appropriate surface antigens to identify macrophages as well as to distinguish their monocyte-derived or tissue-resident characteristics.…”

Voglibose Regulates the Secretion of GLP-1 Accompanied by Amelioration of Ileal Inflammatory Damage and Endoplasmic Reticulum Stress in Diabetic KKAy Mice

“…The known effects of SCFAs in the intestine include enhancing the gut barrier function and exerting anti-inflammatory effects by acting on ileal epithelial cells, enteroendocrine cells and immune cells [11]. To evaluate the effects of voglibose on ileal function, the histological alteration of ileum tissue was evaluated using hematoxylin and eosin (H&E) staining.…”

“…In the healthy intestine, most macrophages maintain anti-inflammatory and resident subpopulations, whereas those with the pro-inflammatory phenotype have elevated expression of the nuclear factor kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α) when eating a high-fat diet (HFD) [9]. Colonic pro-inflammatory macrophages regulate glycemic control in mice fed an HFD as their numbers increase and alter glucose tolerance and peripheral insulin resistance [10,11]. Thus, the differentiation from pro-inflammatory macrophages toward anti-inflammatory subsets initiated by SCFAs could be a novel therapeutic method for T2DM.…”