An Incretin-Dependent Modulation of Periprandial Neutrophilia

Daily cycles of fasting and feeding shape systemic metabolism, yet how innate immunity senses these transitions remains unclear. Chronic high-fat diet (HFD) primes granulocyte-monocyte progenitors to generate clones with heightened inflammasome activity and excessive production of interleukin-6 (IL-6) and IL-1β. Whether periprandial states influence immune surveillance remains unknown. We profiled periprandial immune adaptations in mice fed an HFD (60% energy from fat) or standard-fat diet (SFD) after overnight fasting and up to 4 h postfeeding, integrating blood immunophenotyping, endotoxin challenges, and neutrophil activation markers. Neutrophil counts rose within 15 min of feeding, preceding monocytosis (≥2–4 h). Neutrophilia during SFD, but not HFD, refeeding was associated with lower lipopolysaccharide-induced sickness, suggesting that it is critical for the host to microbial challenges. This early neutrophilia was enhanced by HFD and further amplified with the establishment of insulin resistance following 7 days of HFD feeding. We link this response to intestinal fat absorption and to the coordinated glucagon-like peptide 1 (GLP-1)/insulin regulation of the periprandial responses. Yet, GLP-1 receptor (GLP-1R) antagonism potentiated neutrophilia during HFD feeding, whereas coadministration of insulin abolished it. After 7 days of HFD adaptation, this insulin effect was lost, linking GLP-1 action to insulin sensitivity. In humans, periprandial neutrophilia was also observed, and it was altered in type 2 diabetes, independent from C-reactive protein, IL-6, and IL-1β. Feeding elicits a rapid neutrophil response established to provide immune resilience during nutrient absorption. These findings uncover a GLP-1–insulin-dependent axis coordinating immunometabolic adaptation to the periprandial state. Article Highlights We determine how innate immunity adapts to transitions between fasting and feeding. Feeding rapidly induced periprandial neutrophilia. HFD accelerated this reponse. We therefore sought to examine whether periprandial states regulate neutrophil dynamics. We identified that the glucagon-like peptide 1 and insulin axis modulates the neutrophil surge, which is critical during endotoxin challenges. The periprandial state prepares the host for endotoxemia. We bridge nutrient intake and incretin-sensitive immunity to inflammatory tone, redefining postprandial inflammation, insulin resistance, and cardiometabolic risk in diabetes.