Leptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity

Author(s):Show less -

Monteiro, Lauar de Brito ; Prodonoff, Juliana Silveira ; de Aguiar, Cristhiane Favero ; Correa-da-Silva, Felipe ; Castoldi, Angela ; Bakker, Nikki van Teijlingen ; Davanzo, Gustavo Gastao ; Castelucci, Bianca ; Pereira, Jessica Aparecida da Silva ; Curtis, Jonathan ; Buescher, Joerg ; dos Reis, Larissa Menezes ; Castro, Gisele ; Ribeiro, Guilherme ; Virgilio-da-Silva, Joao Victor ; Adamoski, Douglas ; Gomes Dias, Sandra Martha ; Consonni, Silvio Roberto ; Donato, Jose ; Pearce, Edward J. ; Saraiva Camara, Niels Olsen ; Moraes-Vieira, Pedro M.

• Document type: Journal article
• Source: Diabetes; v. 71, n. 7, p. 16-pg., 2022-07-01.

Abstract

Obesity is a major concern for global health care systems. Systemic low-grade inflammation in obesity is a major risk factor for insulin resistance. Leptin is an adipokine secreted by the adipose tissue that functions by controlling food intake, leading to satiety. Leptin levels are increased in obesity. Here, we show that leptin enhances the effects of LPS in macrophages, intensifying the production of cytokines, glycolytic rates, and morphological and functional changes in the mitochondria through an mTORC2-dependent, mTORC1-independent mechanism. Leptin also boosts the effects of IL-4 in macrophages, leading to increased oxygen consumption, expression of macrophage markers associated with a tissue repair phenotype, and wound healing. In vivo, hyperleptinemia caused by diet-induced obesity increases the inflammatory response by macrophages. Deletion of leptin receptor and subsequently of leptin signaling in myeloid cells (ObR(-/-)) is sufficient to improve insulin resistance in obese mice and decrease systemic inflammation. Our results indicate that leptin acts as a systemic nutritional checkpoint to regulate macrophage fitness and contributes to obesity-induced inflammation and insulin resistance. Thus, specific interventions aimed at downstream modulators of leptin signaling may represent new therapeutic targets to treat obesity-induced systemic inflammation. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/06372-3 - Multiparametric flow cytometry
• Grantee: Alessandro dos Santos Farias
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 18/19338-5 - The study of the metabolic and functional modulation of macrophages by leptin
• Grantee: Lauar de Brito Monteiro
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 16/23328-0 - Study of the metabolic regulation of macrophages by leptin
• Grantee: Lauar de Brito Monteiro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/25973-8 - Mitoimmunity: mitochondria adaptation in pathological and physiological states
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg)
• Grantee: Carlos Frederico Martins Menck
• Support Opportunities: Research Projects - Thematic Grants