Circadian desynchronization alters metabolic and immune responses following lipopolysaccharide inoculation in male mice

Abstract

Metabolism and inflammation are linked at many levels. Sickness behaviors are elicited by the immune system's response to antigenic stimuli, and include changes in feeding and metabolism. The immune system is also regulated by the circadian (daily) clock, which generates endogenous rhythms, and synchronizes these rhythms to the light-dark cycle. Modern society has resulted in chronic misalignment or desynchronization of the circadian clock and the external environment. We have demonstrated that circadian desynchronization (CD) in mice alters metabolic function, and also affects both peripheral and central immune responses following a low-dose lipopolysaccharide (LPS) challenge. However, it is unclear how this altered immune response impacts sickness behaviors and metabolism following challenge. To test this, we housed male mice in circadian desynchronized (10-hours light:10-hours dark) or control (12-hours light:12-hours dark) conditions for 5-6 weeks. We then challenged mice with LPS (i.p., 0.4 mg/kg) or PBS and measured changes in body mass, feeding, drinking and locomotion using a comprehensive phenotyping system. Plasma, liver, and brain were collected 36 h post-inoculation (hpi) and inflammatory messengers were measured via multiplex cytokine/chemokine array and qPCR. We find that recovery of locomotion and body mass is prolonged in CD mice following LPS challenge. Additionally, at 36 hpi the expression of several proinflammatory cytokines differ depending on pre-inoculation lighting conditions. Our findings add to the growing literature which documents how desynchronization of circadian rhythms can lead to disrupted immune responses and changes in metabolic function.

Keywords: Biological rhythms; Lipopolysaccharide; Metabolism; Neuroimmune.