Dynamic and extensive metabolic state-dependent regulation of cytokine expression and circulating levels

Pia S. Petersen, Xia Lei, Marcus M. Seldin, Susana Rodriguez, Mardi S. Byerly, Andrew Wolfe, Scott Whitlock, G. William Wong

Research output: Contribution to journalArticle

Abstract

Cytokines play diverse and critical roles in innate and acquired immunity, and several function within the central nervous system and in peripheral tissues to modulate energy metabolism. The extent to which changes in energy balance impact the expression and circulating levels of cytokines (many of which have pleiotropic functions) has not been systematically examined. To investigate metabolism-related changes in cytokine profiles, we used a multiplex approach to assess changes in 71 circulating mouse cytokines in response to acute (fasting and refeeding) and chronic (high-fat feeding) alterations in whole body metabolism. Refeeding significantly decreased serum levels of IL-22, IL-1α soluble (s)IL-2Rα and soluble vascular endothelial growth factor receptor 3 (VEGFR3), but markedly increased granulocyte colony-stimulating factor (G-CSF), IL-1ß chemokine (C-C motif) ligand (CCL2), sIL-1RI, lipocalin-2, pentraxin-3, tissue inhibitor of metalloproteinase (TIMP-1), and serum amyloid protein (SAP) relative to the fasted state. Interestingly, only a few of these changes paralleled the alterations in expression of their corresponding mRNAs. Functional studies demonstrated that central delivery of G-CSF increased, whereas IL-22 decreased, food intake. Changes in food intake were not accompanied by acute alterations in orexigenic (Npy and Agrp) and anorexigenic (Pomc and Cart) neuropeptide gene expression in the hypothalamus. In the context of chronic high-fat feeding, circulating levels of chemokine (C-X-C) ligand (CXCL1), serum amyloid protein A3 (SAA3), TIMP-1α1-acid glycoprotein (AGP), and A2M were increased, whereas IL-12p40, CCL4, sCD30, soluble receptor for advanced glycation end products (sRAGE), CCL12, CCL20, CX3CL1, IL-16, IL-22, and haptoglobin were decreased relative to mice fed a control low-fat diet. These results demonstrate that both short- and long-term changes in whole body metabolism extensively alter cytokine expression and circulating levels, thus providing a foundation and framework for further investigations to ascertain the metabolic roles for these molecules in physiological and pathological states.

Original languageEnglish (US)
Pages (from-to)R1458-R1470
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume307
Issue number12
DOIs
StatePublished - Dec 15 2014

Keywords

  • Cytokines
  • Fasting
  • Food intake
  • Granulocyte colony-stimulating factor
  • Interleukin-22
  • Metabolism
  • Obesity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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