# ANGPTL8 links refeeding to monocyte dynamics and metabolic inflammation via the CCL5-CCR5 axis

## TL;DR

ANGPTL8 connects feeding to inflammation by increasing monocytes and proinflammatory responses through the CCL5-CCR5 pathway.

## Contribution

ANGPTL8 is identified as a nutritional checkpoint linking refeeding to monocyte dynamics and metabolic inflammation.

## Key findings

- ANGPTL8 overexpression increases monocytes and proinflammatory cytokines, while its deletion reduces them.
- ANGPTL8 promotes CCL5 production via P38 signaling, which drives monocyte recruitment and macrophage polarization.
- Deleting ANGPTL8 improves metabolic function in obese mice, and CCL5 administration reverses these benefits.

## Abstract

Metabolic inflammation is closely linked to dynamic changes in circulating monocyte populations, yet how nutritional signals regulate this process remains unclear. ANGPTL8, a hepatokine rapidly induced by refeeding, emerged as a key regulator of postprandial monocyte dynamics. We examined ANGPTL8 expression in human and murine fasting-refeeding models and manipulated ANGPTL8 expression specifically in hepatocytes to assess its role in metabolic inflammation and insulin resistance in obese mice. ANGPTL8 overexpression elevated levels of circulating monocytes and proinflammatory cytokines, while its deletion reduced these parameters and conferred metabolic benefits. Mechanistically, recombinant ANGPTL8 stimulated CCL5 production in bone marrow–derived macrophages via P38 signaling activation, promoting monocyte recruitment and proinflammatory macrophage polarization. These effects were mitigated by CCR5 antagonism. Rescue experiments demonstrated that CCL5 supplementation in Angptl8-deficient mice restored monocyte levels and inflammatory responses. Functionally, ANGPTL8 worsened insulin resistance and glucose intolerance in obese mice, effects that were reversed by its deletion and recapitulated by CCL5 administration. These findings suggest that ANGPTL8 functions as a nutritional checkpoint that links feeding status to monocyte-mediated inflammation through the CCL5-CCR5 axis. By driving monocytosis and proinflammatory macrophage activation, ANGPTL8 exacerbates metabolic dysfunction. Targeting the ANGPTL8-CCL5-CCR5 pathway may therefore offer a promising therapeutic strategy for managing obesity-related metabolic diseases.

ANGPTL8 links nutritional status to metabolic inflammation by driving monocyte recruitment through the CCL5–CCR5 axis.