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| Author(s): |
Lauar de Brito Monteiro
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2021-04-12 |
| Examining board members: |
Pedro Manoel Mendes de Moraes Vieira;
Vinicius de Andrade Oliveira;
Kelly Grace Magalhães;
Marcelo Alves Mori;
Karina Ramalho Bortoluci
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| Advisor: | Pedro Manoel Mendes de Moraes Vieira |
| Abstract | |
Obesity is now considered one of the main risk factors for several comorbidities, such as type 2 diabetes, autoimmunities and cardiovascular diseases. There is a population of resident macrophages in the adipose tissue responsible for the maintenance of this tissue, which can act in pro-inflammatory (M1-like) responses or in tissue repair (M2-like). In obese individuals, the number of M1-like macrophages increases in proportion to M2-like macrophages, due to the state of chronic subclinical inflammation. Leptin is an adipokine secreted by the adipose tissue that has the function of controlling food intake, leading to satiety. Our hypothesis contemplated the idea that the hyperleptinemia present in obese individuals could induce a pro-inflammatory profile in adipose tissue resident macrophages. In this study, we showed that leptin potentiates the action of LPS in macrophages, intensifying the production of cytokines, glycolytic rates and morphological and functional changes in the mitochondria. This pro-inflammatory effect of leptin depends on the activation of mTOR. Treatment with rapamycin - an mTOR inhibitor - reversed the effects of leptin on cytokine production and, using the CreLox system to generate mice with specific deficiency of mTORC1 (Raptor-/-) and mTORC2 (Rictor-/-) in macrophages, we observed that mTORC2 is necessary for leptin-mediated effects in macrophages. In addition, when macrophages were stimulated with IL-4 for the induction of a repair profile (M2-like), leptin also potentiated the effects of IL-4, leading to increased oxygen consumption and expression of classic M2-like macrophage markers (Il10, Ym1, Fizz1, Mgl1/2, Mrc1 and Arg1). Resident macrophages express the leptin receptor at different levels, and this expression is not modified by obesity. In vivo, hyperleptinemia caused by diet-induced obesity generates an increase in the inflammatory response by macrophages. The deletion of leptin receptor and subsequently of leptin signaling in myeloid cells (ObR-/-) is sufficient to improve insulin resistance in obese mice and decrease the production of inflammatory cytokines by peritoneal macrophages. Our results indicate that leptin regulates the immune function of macrophages and contributes to the development of insulin resistance. We suggest that specific interventions in modulators downstream of leptin signaling may represent new therapeutic targets for obesity (AU) | |
| 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) |