title: Dynamic and extensive metabolic state-dependent regulation of cytokine expression and circulating levels.
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-1β, 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-1, α1-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.
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pia S
authors.initials: PS
authors.lastname: Petersen
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Seldin
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Susana
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mardi S
authors.initials: MS
authors.lastname: Byerly
authors.affiliation: Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolfe
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Scott
authors.initials: S
authors.lastname: Whitlock
authors.affiliation: Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland gwwong@jhmi.edu.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D000818:Animals; D001835:Body Weight; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism / Q000187:drug effects; D005215:Fasting / Q000097:blood*; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000097:blood; D007276:Injections, Intraventricular; D007378:Interleukins / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D019518:Postprandial Period; D012333:RNA, Messenger / Q000097:blood; D015398:Signal Transduction; D013997:Time Factors; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D004041:Dietary Fats; D016179:Granulocyte Colony-Stimulating Factor; D007378:Interleukins; D012333:RNA, Messenger; D000097043:Interleukin-22
keywords: cytokines; fasting; food intake; granulocyte colony-stimulating factor; interleukin-22; metabolism; obesity