CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
Natalia Mendes,
Ariane Zanesco,
Cristhiane Aguiar,
Gabriela F Rodrigues-Luiz,
Dayana Silva,
Jonathan Campos,
Niels Olsen Saraiva Camara,
Pedro Moraes-Vieira,
Eliana Araujo,
Licio A Velloso
Affiliations
Natalia Mendes
School of Medical Sciences, Department of Translational Medicine (Section of Pharmacology), University of Campinas, Campinas, Brazil; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
Ariane Zanesco
Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
Cristhiane Aguiar
Laboratory of Immunometabolism, Institute of Biology - University of Campinas, Brazil, Campinas, Brazil
Gabriela F Rodrigues-Luiz
Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil
Dayana Silva
Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
Jonathan Campos
Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
Niels Olsen Saraiva Camara
Laboratory for Transplantation Immunobiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
Laboratory of Immunometabolism, Institute of Biology - University of Campinas, Brazil, Campinas, Brazil
Eliana Araujo
Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil; Faculty of Nursing, University of Campinas, Campinas, Brazil
Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil; National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro, Brazil
Microgliosis plays a critical role in diet-induced hypothalamic inflammation. A few hours after a high-fat diet (HFD), hypothalamic microglia shift to an inflammatory phenotype, and prolonged fat consumption leads to the recruitment of bone marrow-derived cells to the hypothalamus. However, the transcriptional signatures and functions of these cells remain unclear. Using dual-reporter mice, this study reveals that CX3CR1-positive microglia exhibit minimal changes in response to a HFD, while significant transcriptional differences emerge between microglia and CCR2-positive recruited myeloid cells, particularly affecting chemotaxis. These recruited cells also show sex-specific transcriptional differences impacting neurodegeneration and thermogenesis. The chemokine receptor CXCR3 is emphasized for its role in chemotaxis, displaying notable differences between recruited cells and resident microglia, requiring further investigation. Central immunoneutralization of CXCL10, a ligand for CXCR3, resulted in increased body mass and decreased energy expenditure, especially in females. Systemic chemical inhibition of CXCR3 led to significant metabolic changes, including increased body mass, reduced energy expenditure, elevated blood leptin, glucose intolerance, and decreased insulin levels. This study elucidates the transcriptional differences between hypothalamic microglia and CCR2-positive recruited myeloid cells in diet-induced inflammation and identifies CXCR3-expressing recruited immune cells as protective in metabolic outcomes linked to HFD consumption, establishing a new concept in obesity-related hypothalamic inflammation.
