Metabolic and functional remodeling of colonic macrophages in response to high-fat diet-induced obesity

Angela Castoldi; David E Sanin; Nikki van Teijlingen Bakker; Cristhiane F Aguiar; Lauar de Brito Monteiro; Nisha Rana; Katarzyna M Grzes; Agnieszka M Kabat; Jonathan Curtis; Alanna M Cameron; George Caputa; Tiago Antônio de Souza; Fabrício O Souto; Joerg M Buescher; Joy Edwards-Hicks; Erika L Pearce; Edward J Pearce; Niels Olsen Saraiva Camara

doi:10.1016/j.isci.2023.107719

Metabolic and functional remodeling of colonic macrophages in response to high-fat diet-induced obesity

iScience. 2023 Aug 25;26(10):107719. doi: 10.1016/j.isci.2023.107719. eCollection 2023 Oct 20.

Authors

Angela Castoldi^{1

2

3}, David E Sanin^{2

4}, Nikki van Teijlingen Bakker², Cristhiane F Aguiar¹, Lauar de Brito Monteiro², Nisha Rana², Katarzyna M Grzes^{2

4}, Agnieszka M Kabat^{2

4}, Jonathan Curtis^{2

4}, Alanna M Cameron², George Caputa², Tiago Antônio de Souza¹, Fabrício O Souto³, Joerg M Buescher⁵, Joy Edwards-Hicks², Erika L Pearce^{2

4}, Edward J Pearce^{2

4}, Niels Olsen Saraiva Camara¹

Affiliations

¹ Department of Immunology, University of Sao Paulo, Sao Paulo, Brazil.
² Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany.
³ Institute Keizo Asami, Federal University of Pernambuco, Pernambuco, Brazil.
⁴ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁵ Metabolomics Facility, Max Planck Institute of Epigenetics and Immunobiology, Freiburg im Breisgau, Germany.

Abstract

Little is known about the effects of high-fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1^hiMHCII^hi and were CD4^-TIM4^-. During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid-associated macrophages (LAMs). Via single-cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HFD, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis, and efferocytosis signatures. CX3CR1^hiMHCII^hi colonic resident LPMs had fewer lipid droplets (LDs) and decreased triacylglycerol (TG) content compared to equivalent cells in lean mice and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.

Keywords: Endocrinology; Immune response; Metabolomics.