Presenting Author:

Heekyung Hong, Ph.D.

Principal Investigator:

Joseph Bass, M.D.

Department:

Medicine

Keywords:

Circadian Clock, NF-κB, saturated fat diet, inflammation, genome-wide cistrome

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B43 - Basic Science

Activation of NF-κB Links Nutrition and Inflammation to Circadian Disruption

The molecular clock synchronizes organismal metabolism by driving transcriptional cycles in anticipation of light, and recent studies have shown that diet itself affects the mammalian clock (1,2). At the molecular level, the circadian oscillator is composed of an autoregulatory transcription feedback loop in which transcription factors (TF) in the forward limb (CLOCK/BMAL1) induce the transcription of their own repressors (PER/CRY) in the negative limb in a cycle that repeats itself every 24 hrs (3). Circadian timekeeping in the sleep-wake cycle and physiologic systems is a ubiquitous feature of all animals and allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment. Importantly, ensuing research showed that the core clock TFs play an essential role in the regulation of energy balance, glucose, and lipid metabolism. Insight into the molecular coupling of circadian and metabolic pathways has recently advanced through demonstration that the cis-acting networks (cistromes) of core clock transcription factors exhibit extensive interconnection with metabolic gene networks (4,5). However, it is still not understood how changes in metabolic and nutrient conditions can reset transcriptional or behavioral cycles. Consumption of a high-fat diet and overnutrition are risk factors for obesity and chronic inflammation. Mounting evidence from work in mice has demonstrated that many of the complications of overnutrition, including cardiovascular disease, appetitive dysregulation, prothrombotic state, insulin resistance, and hypoinsulinemia, are mediated through metabolic inflammation induced by activation of NF-κB within both the hypothalamus and distinct peripheral tissues6. Here, we demonstrate that feeding mice a diet enriched in saturated but not unsaturated fat altered neuronal pacemaker function and behavior, corresponding with activation of the inflammation-signaling transcription complex NF-κB and inhibition of circadian transcription mediated by CLOCK/BMAL1. Genetic loss of NF-κB signaling increased CLOCK/BMAL1 chromatin binding and up-regulated expression of the clock repressors PER/CRY. Cistrome analysis showed that activated NF-κB localizes genome-wide to regions regulated by BMAL1 to interfere with expression of clock repressors, while inducible NF-κB ablation in adult mice dramatically disrupted circadian activity and light entrainment. Our results suggest that NF-κB signaling maintains circadian homeostasis in the quiescent state, and that inflammation-induced NF-κB activation leads to circadian disruption independent of overnutrition (6). 1. Kohsaka, A. et al. (2007) Cell Metab 6, 414–421 2. Eckel-Mahan, K. L. et al. (2013) Cell 155, 1464–1478 3. Ko, C.H. and Takahashi, J.S. (2006) Hum. Mol Genet 15, R271-R277 4. Feng, et al. (2011) Science 331, 1315-1319 5. Koike, N. et al. (2012) Science 338, 349-354 6. Arkan, M.C. et al. (2005) Nat Med 11, 191-198