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Leptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity

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posted on 04.04.2022, 16:09 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-Vieira
Obesity 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.


The work was supported by the Sao Paulo research foundation-FAPESP (2013/07607-8, 2015/15262-8, 2016/23328-0, 2019/25973-8, 2019/19435-3, 2018/19338-5, 2019/06372-3, and 2020/16030-0). We also thank the support of Max-Planck Society, the Brazilian National Council for Scientific and Technological Development - CNPq, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) – Finance Code 001.