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Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection

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Abstract

Leptin and glucocorticoids (GCs) are involved in metabolic functions, thymic homeostasis and immune activity through complex interactions. We recently showed that C57BL/6 mice infected with Trypanosoma cruzi revealed a fatal disease associated with a dysregulated immune–endocrine response characterized by weight loss, deleterious synthesis of pro-inflammatory cytokines and GCs-driven thymus atrophy. Extending this study, we now explored the relationship between leptin and GCs, in terms of infection outcome, thymic and metabolic changes. T. cruzi-infected mice showed a food intake reduction, together with hypoglycemia and lipolysis-related changes. Infected animals also displayed a reduction in systemic and adipose tissue levels of leptin, paralleled by a down-regulation of their receptor (ObR) in the hypothalamus. Studies in infected mice subjected to adrenalectomy (Adx) showed a worsened course of infection accompanied by even more diminished systemic and intrathymic leptin levels, for which GCs are necessary not only to decrease inflammation but also to sustain leptin secretion. Adx also protected from thymic atrophy, independently of the reduced leptin contents. Leptin administration to infected mice aggravated inflammation, lowered parasite burden and attenuated GCs release, but did not normalize thymic atrophy or metabolic parameters. Acute T. cruzi infection in C57BL/6 mice coexists with a dysregulation of leptin/hypothalamic ObR circuitry dissociated from body weight and food intake control. Endogenous GCs production attempted to reestablish systemic leptin concentrations, but failed to improve leptin-protective activities at the thymic level, suggesting that the leptin/GCs intrathymic relationship is also altered during this infection.

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Acknowledgments

S.R.V., A.R.P. and O.A.B. are members of The National Council Research (CONICET). R. M. thanks CONICET for a fellowship. This work was supported by grants from the Secretary of Sciences and Technology of National University of Rosario (SCYT-UNR, 1MED-348), National Agency for Scientific and Technological Promotion (ANPCYT, PICT 2008-0980) and Argentine Federation of Cardiology (FAC-GADOR 2011). The authors thank Mrs. Vanina Tartalini for their technical assistance and Gustavo Capriotti from Wiener Lab. Foundation for their help in supplying some laboratory reagents.

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  1. Facultad de Ciencias Médicas, Instituto de Inmunología, Universidad Nacional de Rosario, Santa Fe 3100, 2000, Rosario, Argentina

    Romina Manarin, Silvina Raquel Villar, Rodrigo Fernández Bussy, Florencia Belén González, Eva Verónica Deschutter, Ana Paula Bonantini, Eduardo Roggero, Ana Rosa Pérez & Oscar Bottasso

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  1. Romina Manarin
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  2. Silvina Raquel Villar
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  4. Florencia Belén González
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Correspondence to Romina Manarin or Ana Rosa Pérez.

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Ana Rosa Pérez and Oscar Bottasso contributed equally to this work.

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430_2013_294_MOESM1_ESM.tif

a) Plasma leptin levels in TNF-R1 KO mice compared with wild-type (WT) mice. Values represent the mean ± SEM of 3–5 mice/group/day (one of two independent experiments). Data correspond to results obtained after 14 days post-infection (dpi). b) mRNA expression levels of TNF-α in epididymal fat pads from control and infected animals were analyzed by real-time RT-PCR. The results are expressed as the relative difference to the uninfected control by 2−∆∆CT method. Bars and lines represent the mean ± SEM of 4-6 mice/group. * p < 0.05 vs. the corresponding uninfected group; § p < 0.05 vs. the corresponding uninfected mice; # p < 0.05 vs. 14 dpi; n.d. = non-detectable values. Results are representative of two or three independent experimental rounds, respectively (TIFF 262 kb)

Characteristics of T. cruzi infection in TNF-R1 KO or adrenalectomized mice(DOCX 18 kb)

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Manarin, R., Villar, S.R., Fernández Bussy, R. et al. Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection. Med Microbiol Immunol 202, 339–352 (2013). https://doi.org/10.1007/s00430-013-0294-1

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