Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signaling

Disruption of the circadian rhythm is associated with inflammatory diseases, metabolic syndrome and cancer. In mice, the time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle (Halberg et al. 1960; Marpegan et al. 2009; Nguyen et al. 2013). Myeloid-cell intrinsic circadian clock components control inflammatory cytokine production (Gibbs et al. 2012; Curtis et al. 2015; Bellet et al. 2013), and metabolic inputs influence lethality in response to LPS (Wang et al. 2016; Weis et al. 2017; Traba et al. 2017), but the relative contributions of these inputs to daily changes in sepsis susceptibility are not known. Here we show that feeding, rather than light, controls time of day dependent LPS sensitivity. Mortality following LPS administration after 12 hours of food deprivation was associated with hypoglycemia, rather than inflammatory cytokine production, independent of the clock regulator BMAL1 expressed in myeloid cells. Deletion of BMAL1 in hepatocytes globally disrupted the transcriptional response to the feeding cycle in the liver and resulted in constitutively high LPS sensitivity. These results show that food, rather than light, is the ‘zeitgeber’ for acute mortality in response to LPS, with a critical role for the hepatocyte-intrinsic circadian clock in integrating nutritional cues to regulate survival in response to innate immune stimuli. Understanding the hepatic molecular programs operational in response to fasting versus fed cues could identify novel pathways that may be targeted to enhance resistance to endotoxemia. Mice were housed under stable 12 h dark 12 h light conditions and ad libitum feeding for at least a week before access to food was restricted to either the day-time (DF, food from ZT0 to ZT12) or the night-time (NF, food from ZT12 to ZT0). The amount of food was thereby not restricted and normal chow was fed. On day 5 of the time restricted feeding schedule, mice were euthanized at ZT0 or ZT12 and liver samples harvested for RNA isolation.