β7-Integrin worsens diet-induced metabolic syndrome in mice by altering intestinal lipid handling and colonic inflammatory monocyte infiltration

Western diet (WD)-induced metabolic syndrome (MetS) involves obesity, insulin resistance, dyslipidemia, and low-grade inflammation. While β7 integrin-expressing adaptive immune cells contribute to WD-induced MetS, the role of β7 integrin in innate immunity remains unclear. To address this, the effect of antibody-mediated β7 integrin blockade or β7 integrin deficiency on WD-induced MetS was studied in recombination activating gene-2-deficient mice. Loss or inhibition of β7 integrin protected mice from WD-induced obesity, dyslipidemia, and glucose intolerance, partially via loss of β7 integrin-MAdCAM-1 interactions. β7 integrin deficiency altered intestinal lipid handling and monocyte infiltration into the colon and adipose tissue. Adoptive transfer confirmed that β7-expressing monocytes promote metabolic dysfunction in WD-fed recipients. Phospho-signaling analyses revealed attenuated PI3K-Akt pathway activation in β7 integrin-deficient colonic macrophages, and antibody treatments caused minor shifts in fecal microbiota profiles. Thus, β7 integrin-expressing innate immune cells drive WD-induced metabolic inflammation through monocyte recruitment, macrophage activation, and altered intestinal fat metabolism.