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Leptin Corrects Host Defense Defects after Acute Starvation in Murine Pneumococcal Pneumonia

Departments of Environmental Health Sciences, Internal Medicine, and Microbiology and Immunology, University of Michigan; and VA Medical Center, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Peter Mancuso, Ph.D., University of Michigan, 1420 Washington Heights, Department of Environmental Health Sciences SPH II, Ann Arbor, MI 48109-2029. E-mail: pmancuso{at}umich.edu

Rationale: Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.

Objectives: To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.

Methods: C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 µg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10⁵ cfu of Streptococcus pneumoniae via the intranasal route.

Measurements and Main Results: Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore–stimulated leukotriene B₄ synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B₄ synthesis.

Conclusions: These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.

Key Words: leptin • malnutrition • pneumonia • Streptococcus pneumoniae

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