Peripheral leptin signaling persists in innate immune cells during diet-induced obesity

Author(s):Show less -

Souza-Almeida, Glaucia ^{[1, 2]} ; Palhinha, Lohanna ^[1] ; Liechocki, Sally ^[1] ; da Silva Pereira, Jessica Aparecida ^{[3, 1, 4]} ; Reis, Patricia Alves ^[1] ; Braga Dib, Paula Ribeiro ^{[5, 6]} ; Hottz, Eugenio D. ^{[1, 5]} ; Gameiro, Jacy ^[6] ; Vallochi, Adriana Lima ^[1] ; de Almeida, Cecilia Jacques ^[1] ; Castro-aria-Neto, Hugo ^[1] ; Bozza, Patricia T. ^[1] ; Maya-Monteiro, Clarissa Menezes ^[1]

Affiliation

^[1] Oswaldo Cruz Fdn FIOCRUZ, Oswaldo Cruz Inst, Lab Immunopharmacol, Rio De Janeiro, RJ - Brazil

^[2] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Immunoinflammat, Campinas, SP - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[4] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Immunometab, Campinas - Brazil

^[5] Univ Fed Juiz de Fora, Dept Biochem, Lab Immunothrombosis, Juiz De Fora, MG - Brazil

^[6] Univ Fed Juiz de Fora, Dept Parasitol Microbiol & Immunol, Lab Immunol Infect Dis & Obes, Juiz De Fora, MG - Brazil

• Document type: Journal article
• Source: Journal of Leukocyte Biology; v. 109, n. 6, p. 1131-1138, JUN 2021.
• Web of Science Citations: 2

Abstract

Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally. Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-alpha- and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14-16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normal-sucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-alpha and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND- or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease. (AU)

• FAPESP's process: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 19/04780-7 - AHR and LXR Transcriptional factors as targets to treat immune-mediated degenerative diseases
• Grantee: Jéssica Aparecida da Silva Pereira
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 17/00079-7 - Effects of LXRs receptor activation on systemic metabolic parameters and on the metabolic modulation of resident tissue macrophages of adipose tissue
• Grantee: Jéssica Aparecida da Silva Pereira
• Support Opportunities: Scholarships in Brazil - Doctorate