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Leptin signaling impairs macrophage defenses against Salmonella Typhimurium

Journal article
Authors J. Fischer
Saray Gutiérrez
R. Ganesan
C. Calabrese
R. Ranjan
G. Cildir
N. J. Hos
J. Rybniker
M. Wolke
J. W. U. Fries
V. Tergaonkar
G. Plum
A. Antebi
N. Robinson
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 116
Issue 33
Pages 16551-16560
ISSN 0027-8424
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Physiology
Pages 16551-16560
Language en
Keywords macrophages, leptin, Salmonella, AKT, lysosomes, host-defense, infection, receptor, cells, activation, expression, lysosome, pathogen
Subject categories Pharmaceutical Sciences


The dynamic interplay between metabolism and immune responses in health and disease, by which different immune cells impact on metabolic processes, are being increasingly appreciated. However, the potential of master regulators of metabolism to control innate immunity are less understood. Here, we studied the cross-talk between leptin signaling and macrophage function in the context of bacterial infections. We found that upon infection with Gram-negative pathogens, such as Salmonella Typhimurium, leptin receptor (Lepr) expression increased in both mouse and human macrophages. Unexpectedly, both genetic Lepr ablation in macrophages and global pharmacologic leptin antagonization augmented lysosomal functions, reduced S. Typhimurium burden, and diminished inflammation in vitro and in vivo. Mechanistically, we show that leptin induction activates the mTORC2/Akt pathway and subsequently down-regulates Phlpp1 phosphatase, allowing for phosphorylated Akt to impair lysosomal-mediated pathogen clearance. These data highlight a link between leptin signaling, the mTORC2/Phlpp1/Akt axis, and lysosomal activity in macrophages and have important therapeutic implications for modulating innate immunity to combat Gram-negative bacterial infections.

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