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Leptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity

2022; American Diabetes Association; Volume: 71; Issue: 7 Linguagem: Inglês

10.2337/db21-0842

1939-327X

Lauar de Brito Monteiro, Juliana Silveira Prodonoff, Cristhiane Fávero de Aguiar, Felipe Corrêa‐da‐Silva, Ângela Castoldi, Nikki van Teijlingen Bakker, Gustavo Gastão Davanzo, Bianca Gazieri Castelucci, Jéssica Aparecida da Silva Pereira, Jonathan D. Curtis, Jörg Büscher, Larissa Menezes dos Reis, Gisele Castro, Guilherme Ribeiro, João Victor Virgílio-da-Silva, Douglas Adamóski, Sandra Martha Gomes Dias, Sílvio Roberto Consonni, José Donato, Edward J. Pearce, Niels Olsen Saraiva Câmara, Pedro M. Moraes‐Vieira,

Adipose Tissue and Metabolism

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.