Chronic low-grade inflammation and activation of the nutrient sensitive intracellular mTOR signaling pathway are majorly involved in the development of obesity and associated insulin resistance. The interrelationships between mTOR and inflammation on obesity conditions, however, have not been investigated. Thus, the main goal of this research proposal is to investigate the involvement of mTOR complex 1 in the control of macrophage function and its involvement in the genesis and maintenance of chronic low-grade inflammation associated with obesity. For this, in vivo experiments with loss of function of the mTOR complex 1 (pharmacological inhibition with rapamycin) will be induced in mice made obese by a high fat diet where we will evaluate: 1) glucose and insulin tolerance; 2) insulin and toll-like receptor intracellular signaling in macrophages and adipocytes; 3) plasma levels of cytokines and metabolites; 4) adipose tissue cellular composition; 5) macrophage recruitment and activation in adipose tissue; 6) macrophages transition from quiescent M2 to the proinflammatory M1 state; 7) macrophage basal and stimulated cytokine secretion; 8) macrophage triacylglycerol synthesis and activity of lipogenic enzymes; and 9) macrophage and adipocyte gene expression profile regarding transcription factors and related co-activators of cytokine production and lipid synthesis. Items 2, 7, 8 and 9 will be also investigated in vitro in RAW 264.7 cells (immortalized macrophage cell lineage) and primary macrophages derived from bone marrow or peritoneum upon mTOR complex 1 genetic and pharmacologic activation and/or inhibition.
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