Fig. 2. Mechanisms of intestinal immune cell-driven metabolic dysfunction.

During obesity, intestinal immune cells contribute to insulin resistance and/or glucose dysregulation, via at least three potential mechanisms. A Changes in immune compartments in the presence of an obesogenic diet promote leakage of bacterial products. This intestinal permeability is facilitated through local changes in cytokines, such as increases in pro-inflammatory cytokines interferon (IFN)γ and tumor-necrosis factor (TNF), coupled with a loss in anti-inflammatory and barrier protective cytokines interleukin (IL)-17, IL-22, and IL-10, anti-microbial peptides (AMPs) and epithelial mucin. Changes in such factors also contribute to the degradation of epithelial tight junction proteins. Increased leakage of bacterial products can drain into metabolic tissues, such as the visceral adipose tissue (VAT) and liver, where they further stimulate local immune cells, such as hepatic Kupffer cells and VAT M1-like macrophages, further enhancing their pro-inflammatory profile and leading to systemic insulin resistance. B Intestinal lymphocytes can potentially sequester gastrointestinal hormones such as glucagon-like peptide (GLP)1, via their GLP1 receptor (GLP1R), thereby limiting its bioavailability and further contributing to metabolic dysfunction. C Finally, evidence indicates that some intestinal immune cells, such as anti-inflammatory IgA⁺ antibody-secreting cells (ASCs), can potentially migrate to distant inflamed sites in the body, resulting in the reduced intestinal presence of ASC products such as IL-10 and IgA.