Day/night variations of high-molecular-weight adiponectin and lipocalin-2 in healthy men studied under fed and fasted conditions

Aims/hypothesis: Adiponectin and lipocalin-2 are adipocyte-derived plasma proteins that have been proposed to have opposite effects on insulin sensitivity. Given the epidemiological, physiological and molecular links between sleep, the circadian timing system and glucose metabolism, the aim of this study was to assess effects of the sleep/wake cycle and the fasting/feeding cycle on high-molecular-weight adiponectin (HMW-adiponectin; the biologically active form) and lipocalin-2. We also aimed to compare the 24 h rhythms in the levels of these proteins with those of cortisol, leptin, leptin-binding protein and total adiponectin. Methods: Lean men underwent a 3 day in-laboratory study, either in the fed state (n=8, age: 20.9±2.1 years, BMI: 22.8±2.3 kg/m²) or fasting state (3 day fast, n=4, age: 25.3±3.9 years, BMI: 23.3±2.2 kg/m²). The sleep episode was scheduled in darkness from 23:00 to 07:00 hours. Blood was sampled every 15 min for 24 h on the third day of each study. Results: While fed, HMW-adiponectin and lipocalin-2 had large daily rhythms with troughs at night (HMW-adiponectin: ~04:00 hours, peak-to-trough amplitude 36%, p<0.0001; lipocalin-2: ~04:00 hours, 40%, p<0.0001). On the third day of fasting, the timing and relative amplitudes were unchanged (HMW-adiponectin: ~04:00 hours, 38%, p=0.0014; lipocalin-2: ~05:00 hours, 38%, p=0.0043). Conclusions/interpretation: These data show that HMW-adiponectin and lipocalin-2 both have significant day/night rhythms, both with troughs at night, that these are not driven by the feeding/fasting cycle, and that it is important to report and/or standardise the time of day for such assays. Further studies are required to determine whether the daily rhythm of HMW-adiponectin levels influences the daily rhythm of insulin sensitivity. Trial registration: ClinicalTrials.gov NCT00140205 Funding: The study was funded by National Institutes of Health (NIH) grant numbers DK58785, DK79929 and DK081913 (to C. S. Mantzoros), and M01-RR-01032, Harvard Clinical and Translational Science Center UL1-RR025758, Center for Nutritional Research Charitable Trust. F. A. J. L. Scheer was supported by NIH grant number P30HL101299 and Brigham and Women's Hospital, Biomedical Research Institute Fund to Sustain Research Excellence, and S. A. Shea was supported by NIH grant number K24-HL076446.