Elevated FGF-21 during Circadian Misalignment in Healthy Humans

Circadian misalignment—sleeping during the biological day and eating at a time when the internal circadian clock promotes sleep—is a risk factor for obesity and diabetes, implicating circadian misalignment as a metabolic stressor. Fibroblast growth factor 21 (FGF-21) is a hepatokine secreted in response to stress and found to be elevated in human obesity and diabetes. Activation of peroxisome proliferator-activator receptor alpha by free fatty acids (FFA), can induce the expression of FGF-21 expression. It has been previously reported that circadian misalignment results in elevated fasting FFA. However, the impact of circadian misalignment on FGF-21 has not been explored. Fourteen healthy adults (6M; aged 26.4±1.2y, BMI 22.7±0.5 kg/m2; mean±SD) participated in a simulated shift-work protocol using a consecutive study design to examine the impact of circadian misalignment on diabetes- and obesity-related risk factors. Participants were provided with a 3d energy balance diet prior to admission and during the 5d inpatient study. Identical meals were consumed each day to minimize the effects of dietary intake on metabolic hormones. Blood was sampled every 1-2 hours for 24 hours during circadian alignment and circadian misalignment and assayed for melatonin and FGF-21. The melatonin rhythm was used as a marker of the master circadian clock and was unchanged during simulated shift-work, indicating circadian misalignment. Circadian misalignment led to elevated FGF-21 during scheduled wake (+123±41% mean±SEM; p<0.01) and across 24h (+36±16%; p<0.05) relative to circadian alignment. Circadian misalignment triggers a stress response that includes an increase in circulating FGF-21. The physiological implications of acute elevations in FGF-21 are unknown, and may contribute to metabolic dysregulation associated with circadian misalignment. Disclosure J.L. Broussard: Advisory Panel; Self; National Institutes of Health. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Sleep Research Society, Society in Science-The Branco Weiss Fellowship. S.J. Morton: None. K. Markan: None. A.W. McHill: None. J. Higgins: None. E. Melanson: None. K. Wright: Advisory Panel; Self; National Institutes of Health, Torvec, Inc. Research Support; Self; National Institutes of Health, Office of Naval Research, Pacific-12 Conference, SomaLogic, Inc. Other Relationship; Self; Circadian Therapeutics, Inc., Kellogg Company, Torvec, Inc. Funding National Institutes of Health (UL1RR025780, P30DK048520); Sleep Research Society Foundation; Branco Weiss Fellowship Society in Science (K01DK110138, R21DK092624)