Abstract
The human circadian system regulates hunger independently of behavioral factors, resulting in a trough in the biological morning and a peak in the biological evening. However, the role of the only known orexigenic hormone, ghrelin, in this circadian rhythm is unknown. Furthermore, although shift work is an obesity risk factor, the separate effects of the endogenous circadian system, the behavioral cycle, and circadian misalignment on ghrelin has not been systematically studied. Here we show—by using two 8-day laboratory protocols—that circulating active (acylated) ghrelin levels are significantly impacted by endogenous circadian phase in healthy adults. Active ghrelin levels were higher in the biological evening than the biological morning (fasting +15.1%, P = 0.0001; postprandial +10.4%, P = 0.0002), consistent with the circadian variation in hunger (P = 0.028). Moreover, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial active ghrelin levels (+5.4%; P = 0.04). While not significantly influencing hunger (P > 0.08), circadian misalignment increased appetite for energy-dense foods (all P < 0.05). Our results provide possible mechanisms for the endogenous circadian rhythm in hunger, as well as for the increased risk of obesity among shift workers.
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References
Scheer FA, Morris CJ, Shea SA. The internal circadian clock increases hunger and appetite in the evening independent of food intake and other behaviors. Obesity. 2013;21:421–3.
Spiegel K, Tasali E, Leproult R, Scherberg N, Van Cauter E. Twenty-four-hour profiles of acylated and total ghrelin: relationship with glucose levels and impact of time of day and sleep. J Clin Endocrinol Metab. 2011;96:486–93.
Espelund U, Hansen TK, Hojlund K, Beck-Nielsen H, Clausen JT, Hansen BS, et al. Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects. J Clin Endocrinol Metab. 2005;90:741–6.
LeSauter J, Hoque N, Weintraub M, Pfaff DW, Silver R. Stomach ghrelin-secreting cells as food-entrainable circadian clocks. Proc Natl Acad Sci USA. 2009;106:13582–7.
Natalucci G, Riedl S, Gleiss A, Zidek T, Frisch H. Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern. Eur J Endocrinol. 2005;152:845–50.
Pan A, Schernhammer ES, Sun Q, Hu FB. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLoS Med. 2011;8:e1001141.
Cain SW, Filtness AJ, Phillips CL, Anderson C. Enhanced preference for high-fat foods following a simulated night shift. Scand J Work Environ Health. 2015;41:288–93.
Bonnell EK, Huggins CE, Huggins CT, McCaffrey TA, Palermo C, Bonham MP. Influences on dietary choices during day versus night shift in shift workers: a mixed methods study. Nutrients. 2017;9:193
Benelam B. Satiation, satiety and their effects on eating behaviour. Nutr Bull. 2009;34:126–73.
Morris CJ, Garcia JI, Myers S, Yang JN, Trienekens N, Scheer FA. The human circadian system has a dominating role in causing the morning/evening difference in diet-induced thermogenesis. Obesity. 2015;23:2053–8.
Morris CJ, Yang JN, Garcia JI, Myers S, Bozzi I, Wang W, et al. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. Proc Natl Acad Sci USA. 2015;112:E2225–34.
Seoane LM, Al-Massadi O, Barreiro F, Dieguez C, Casanueva FF. Growth hormone and somatostatin directly inhibit gastric ghrelin secretion. Vitr Organ Cult Syst J Endocrinol Invest. 2007;30:RC22–5.
Rogers PJ, Hardman CA. Food reward. What it is how meas it Appetite. 2015;90:1–15.
Schiavo-Cardozo D, Lima MM, Pareja JC, Geloneze B. Appetite-regulating hormones from the upper gut: disrupted control of xenin and ghrelin in night workers. Clin Endocrinol. 2013;79:807–11.
Buxton OM, Cain SW, O’Connor SP, Porter JH, Duffy JF, Wang W, et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci Transl Med. 2012;4:129ra143.
McHill AW, Melanson EL, Higgins J, Connick E, Moehlman TM, Stothard ER, et al. Impact of circadian misalignment on energy metabolism during simulated nightshift work. Proc Natl Acad Sci USA. 2014;111:17302–7.
Gonnissen HK, Rutters F, Mazuy C, Martens EA, Adam TC, Westerterp-Plantenga MS. Effect of a phase advance and phase delay of the 24-h cycle on energy metabolism, appetite, and related hormones. Am J Clin Nutr. 2012;96:689–97.
Baldelli R, Bellone S, Castellino N, Petri A, Rapa A, Vivenza D, et al. Oral glucose load inhibits circulating ghrelin levels to the same extent in normal and obese children. Clin Endocrinol. 2006;64:255–9.
Kentish SJ, Frisby CL, Kennaway DJ, Wittert GA, Page AJ. Circadian variation in gastric vagal afferent mechanosensitivity. J Neurosci. 2013;33:19238–42.
Buijs FN, Guzman-Ruiz M, Leon-Mercado L, Basualdo MC, Escobar C, Kalsbeek A, et al. Suprachiasmatic nucleus interaction with the arcuate nucleus; essential for organizing physiological rhythms. eNeuro. 2017;4:0028–17.
Qian J, Dalla Man C, Morris CJ, Cobelli C, Scheer FAJL. Differential effects of the circadian system and circadian misalignment on insulin sensitivity and insulin secretion in humans. Diabetes, Obesity and Metabolism. 2018;20:2481–2485.
McHill AW, Hull JT, McMullan CJ, Klerman EB. Chronic Insufficient Sleep Has a Limited Impact on Circadian Rhythmicity of Subjective Hunger and Awakening Fasted Metabolic Hormones. Frontiers in Endocrinology. 2018;9.
Chellappa SL, Morris CJ, Scheer FAJL. Daily circadian misalignment impairs human cognitive performance task-dependently. Scientific Reports. 2018;8.
Li P, Morris CJ, Patxot M, Yugay T, Mistretta J, Purvis TE, Scheer FAJL, Hu K. Reduced Tolerance to Night Shift in Chronic Shift Workers: Insight From Fractal Regulation. Sleep 2017;40.
Morris CJ, Purvis TE, Hu K, Scheer FAJL. Circadian misalignment increases cardiovascular disease risk factors in humans. Proceedings of the National Academy of Sciences. 2016;113:E1402–E1411.
Acknowledgements
We thank the research volunteers and Brigham and Women’s Hospital’s Center for Clinical Investigation nursing and technical staff. This study was supported by NIH Grant R01HL094806 (FAJLS) and UL1RR025758 (to Harvard University and Brigham and Women’s Hospital). J.Q. was supported in part by American Diabetes Association grant #1-17-PDF-103 (JQ). RC was supported in part by the Minerva Scholarship and the Trustee Fund. MG was supported in part by The Spanish Government of Investigation, Development and Innovation (SAF2017-84135-R) including FEDER co-funding, and NIDDK R01DK105072. FAJLS was supported in part by NIH grants R01HL094806, R01HL118601, R01DK099512, R01DK102696, and R01DK105072 (FAJLS).
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CJM reports receiving salary from Grünenthal Ltd, UK., which relationship is not related to the present article. FAJLS received speaker fees from Bayer Healthcare, Sentara Healthcare, Philips, Kellogg Company, Vanda Pharmaceuticals, and Pfizer. The remaining authors declare that they have no conflict of interest.
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Qian, J., Morris, C.J., Caputo, R. et al. Ghrelin is impacted by the endogenous circadian system and by circadian misalignment in humans. Int J Obes 43, 1644–1649 (2019). https://doi.org/10.1038/s41366-018-0208-9
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DOI: https://doi.org/10.1038/s41366-018-0208-9
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