Targeting colonic macrophages as a potential therapeutic option in metabolic disease

Obesity is characterized by chronic low-grade inflammation. However, the initiating mechanisms remain poorly understood. Here, we characterized intestinal macrophage subpopulations and their role in high-fat diet (HFD)-induced obesity in mice and humans. Pro-inflammatory/monocyte-derived intestinal macrophages transiently increased upon food intake and became chronically elevated upon HFD, suggesting a link between macrophage numbers and glycemia. Indeed, pharmacological dose-dependent or genetic ablation of macrophages improved glucose homeostasis. In particular, colon-specific macrophage depletion improved glycemic control and ameliorated β-cell function. Intestinal macrophage activation upon HFD was characterized by a strong interferon signature and metabolic shift, potentially via mTOR activation. Accordingly, colon-specific mTOR-inhibition enhanced insulin and GLP-1 secretion. In obese humans, pro-inflammatory intestinal macrophages were also increased, potentially by enhanced monocyte recruitment. Taken together, these data reveal that intestinal innate immunity contributes to glycemic dysfunction in obesity. Therefore, specifically targeting colonic macrophages or their activation might be a novel therapeutic avenue to improve glycemic control.