Dynamic and extensive metabolic state-dependent regulation of cytokine expression and circulating levels.
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 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 re-feeding) and chronic (high-fat feeding) alterations in whole-body metabolism. Re-feeding significantly decreased serum levels of IL-22, IL-1?, sIL-2R?, and sVEGFR3, but markedly increased G-CSF, IL-1?, CCL2, sIL-1RI, lipocalin-2, pentraxin-3, TIMP-1, and 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 CXCL1, SAA3, TIMP-1, AGP, and A2M were increased, whereas IL-12p40, CCL4, sCD30, sRAGE, CCL12, CCL20, 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 for further investigations to ascertain the metabolic roles for these molecules in physiological and pathological states.