Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival During Cancer Cachexia Syndrome

Henriques, F.; Lopes, M.; Franco, F.; Knobl, P.; Santos, K.; Bueno, L.; Correa, V.; Bedard, A.; Guilherme, A.; Birbrair, A.; Peres, S.; Farmer, S.; Batista, M. L.

doi:10.1101/400135

bioRxiv · 10.1101/400135

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival During Cancer Cachexia Syndrome

Henriques, F.·Lopes, M.·Franco, F.·Knobl, P.·Santos, K.·Bueno, L.·Correa, V.·Bedard, A.·Guilherme, A.·Birbrair, A.·Peres, S.·Farmer, S.·Batista, M. L.

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Abstract

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that Toll-like receptor 4 (TLR4) mediates AT remodeling, in particular, AT browning and inflammatory response in mice bearing Lewis lung carcinoma (LLC). LLC tumor-bearing (TB) TLR4-/- mice were spared from AT remodeling due to a reduced macrophage infiltration and adipocyte atrophy. TLR4-/- mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 reproduced the main protective effect against AT remodeling found in TLR4-/- TB mice. Moreover, the treatment was effective in prolonging the survival and attenuating tumor mass growth when compared to non-treated-TB animals. Further, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising therapeutic target for cancer-induced AT remodeling.\n\nHIGHLIGHTSO_LIGenetic ablation and pharmacological inhibition of TLR4 attenuate adipose tissue remodeling during cancer-associated cachexia;\nC_LIO_LITLR4 suppression play an essential role in the browning phenotype induced by cachexia;\nC_LIO_LIAdministration of TLR4 drug inhibitor increase survival and reduces tumor mass growth in tumor bearing mice;\nC_LIO_LITLR4 pathway is a promising target for cancer-cachexia therapeutic intervention.\nC_LI

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Henriques, F., Lopes, M., Franco, F., Knobl, P., Santos, K., Bueno, L., Correa, V., Bedard, A., Guilherme, A., Birbrair, A., Peres, S., Farmer, S., Batista, M. L.. 2018-08-25. Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival During Cancer Cachexia Syndrome. https://doi.org/10.1101/400135

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