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ResearchIn-Press PreviewImmunologyMetabolism Open Access | 10.1172/jci.insight.196605

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

Ran-Ran Kan,1 Si-Yi Wang,1 Xiao-Yu Meng,1 Li Huang,1 Yu-Xi Xiang,1 Bei-Bei Mao,1 Hua-Jie Zou,1 Ya-Ming Guo,1 Li-Meng Pan,1 Pei-Qiong Luo,1 Yan Yang,1 Zhe-Long Liu,1 De-Lin Ma,1 Wen-Jun Li,2 Yong Chen,1 Dan-Pei Li,1 and Xue-Feng Yu1

1Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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1Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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2Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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2Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Published November 25, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.196605.
Copyright © 2025, Kan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 25, 2025 - Version history
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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 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 linking 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.

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