Abstract Background Daily cycles of fasting and feeding shape systemic metabolism, yet how innate immunity senses these transitions—and how this intersects with cardiometabolic disease—remains unclear. Chronic high-fat diet (HFD) primes granulocyte–monocyte progenitors (GMPs) to generate myeloid clones with heightened inflammasome activity and excessive interleukin-6 (IL-6) and interleukin-1β (IL-1β) production, pathways strongly implicated in atherosclerosis, insulin resistance, and cardiometabolic inflammation. However, whether physiological periprandial transitions acutely modulate innate immune surveillance in ways that could influence cardiometabolic risk has not been explored. Purpose We sought to investigate if and how physiological periprandial states influence immune surveillance and whether these responses are altered during early metabolic adaptation to HFD feeding. Methods We profiled periprandial immune adaptations in mice fed high-fat diet (HFD, 60% energy from fat) or standard diet (SFD) after overnight fasting and up to 4 h post-feeding, integrating blood immunophenotyping, plasma proteomics, neutrophil activation markers, and bone marrow (BM) GMP transcriptomics. Results Neutrophil counts rose within 15 min of feeding and persisted in circulation via Cxcr4-dependent retention, preceding monocytosis (≥2–4 h). This rapid neutrophil response was enhanced by HFD and further amplified after seven days of HFD adaptation, paralleling the onset of insulin resistance and transcriptional activation of GMPs toward pro-inflammatory programs. The response depended on intestinal lipid absorption, as systemic lipid delivery alone was insufficient to trigger it. Glucagon-like peptide-1 (GLP-1) signaling constrained this periprandial neutrophilia: GLP-1R antagonism potentiated neutrophil expansion during HFD feeding, whereas co-administration of insulin abolished it. After 7 days of HFD adaptation, this insulin sensitivity was lost, linking incretin action to early immunometabolic dysfunction. In 310,000 humans (UKBiobank), postprandial neutrophilia correlated with rises in glucose and triglycerides—key cardiometabolic risk markers—but not with C-reactive protein, IL-6, or IL-1β. Conclusions Feeding elicits a rapid, incretin-sensitive neutrophil mobilization that precedes monocyte recruitment, coupling nutrient absorption with innate immune surveillance. This axis is exaggerated during early HFD adaptation, coinciding with insulin resistance and GMP activation, two hallmarks of cardiometabolic and cardiovascular disease progression. These findings identify a GLP-1–dependent immunometabolic mechanism linking postprandial nutrient handling to leukocyte dynamics and highlight periprandial neutrophilia as a potential early immune biomarker and mechanistic contributor to cardiometabolic risk.
Baragetti et al. (Fri,) studied this question.