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Download fileLeptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity
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posted on 2022-04-04, 16:09 authored by Lauar de Brito Monteiro, Juliana Silveira Prodonoff, Cristhiane Favero de Aguiar, Felipe Correa-da-Silva, Angela Castoldi, Nikki van Teijlingen Bakker, Gustavo Gastão Davanzo, Bianca Castelucci, Jéssica Aparecida da Silva Pereira, Jonathan Curtis, Jörg Büscher, Larissa Menezes dos Reis, Gisele Castro, Guilherme Ribeiro, João Victor Virgílio-da-Silva, Douglas Adamoski, Sandra Martha Gomes Dias, Silvio Roberto Consonni, Jose Donato Jr, Edward J. Pearce, Niels Olsen Saraiva Câmara, Pedro Manoel Moraes-VieiraObesity is a major
concern for global healthcare 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.