Leptin, from the Greek leptos, meaning thin (in reference to its ability to reduce body fat stores), is a hormone secreted primarily by adipocytes. At one time, leptin was portrayed as a potential means of combating obesity. Recently, leptin has been identified as a potent inhibitor of bone formation, acting through the central nervous system. Since numerous studies clearly show that bone remodeling is circadian rhythmic with peak activity during sleep, it is of interest to explore circadian variability in serum leptin. Accordingly, circadian characteristics of serum leptin were examined in 7 clinically healthy men and 4 obese men with type II diabetes. Blood samples were collected for 24 h at 3 h intervals beginning at 19:00. The dark (sleep) phase of the light-dark cycle extended from 22:30 to 06:30, with brief awakening for sampling at 01:00 and 04:00. Subjects consumed general hospital meals (2400 calories) at 16:30, 07:30, and 13:30. Serum leptin levels were determined by a R&D Systems enzyme immunoassay technique. Data were analyzed by linear least-squares estimation using the population multiple components method. A statistically significant (P < .018) circadian rhythm modeled by a single 24 h cosine curve characterized the data of each group. The 24 h mean leptin level was statistically greater (P < .001) in the obese diabetic men than in the healthy men (9.47 +/- 0.66 ng/mL vs. 24.07 +/- 1.71 ng/mL, respectively). Higher leptin levels occurred between midnight and roughly 02:30, and lowest leptin levels occurred between noon and the early afternoon. The phasing of this rhythm is similar to the circadian rhythm in bone remodeling previously described. Our results suggest the findings from a single morning blood sampling for leptin may be misleading since it may underestimate the mean 24 h and peak concentrations of the hormone.

Kanabrocki, E. L.; Hermida, R. C.; McCormick, J. B.; Bremner, F. W.; Third, J. L.H.C.; Ryan, M.; Shirazi, P.; Nemchausky, B. A.; Scheving, L. E. Author Information

amplitude (P Ͻ 0.005) were noted in the older group for all three peptides.A highly significant inverse correlation was found between the values of the three peptides and systolic and diastolic BP (P Ͻ 0.007).LANP, VSDL, and ANF exhibit a highly significant circadian variation as well as a significant decline with age.The present findings indicate that these BP lowering hormones are present in high concentrations in the early morning hours and in significantly lower concentrations throughout the day, in keeping with their inverse relation with BP.

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Atrial natriuretic peptides are a family of hormones synthesized within the same prohormone secreted mainly within the atrium of the heart. These peptides correlate inversely with blood pressure (BP) in humans throughout the day. The increase in BP with increasing age could thus be associated with a decrease in these hormones as the person ages. The present investigation was designed to determine if these peptides, i.e., long acting natriuretic peptide (LANP), vessel dilator (VSDL) and atrial natriuretic factor (ANF), exhibit differing circadian characteristics in men as a function of age. The LANP, VSDL, and ANF were obtained from blood sampled every 3-hr for 24-hrs in men housed in a hospital setting at 3 different ocassions, 5 years apart. Seven men were studied 3 times; 4 in 2 ocassions, and 4 participated once. BP was always obtained by ambulatory monitoring at 15-min intervals. Lights were off at 22:30 h and on at 06:30 h. Hospital meals (2400 cal) were served at 16:30, 07:30 and 13:30 h. Circadian characteristics of hormones and BP in groups of subjects divided by age (<55, 19 profiles; and >55 years, 14 profiles) were established by population multiple-component analysis [Fernández JR, Hermida RC. Chronobiol Internat 1998;15:191–204]. A significant high amplitude rhythm (P < 0.001) was demonstrated for the three peptides in each age-group, with highest values consistently obtained at about 05:30 h. Significant declines in daily mean and amplitude (P < 0.005) were noted in the older group for all three peptides. A highly significant inverse correlation was found between the values of the three peptides and systolic and diastolic BP (P < 0.007). LANP, VSDL, and ANF exhibit a highly significant circadian variation as well as a significant decline with age. The present findings indicate that these BP lowering hormones are present in high concentrations in the early morning hours and in significantly lower concentrations throughout the day, in keeping with their inverse relation with BP.

Kanabrocki, E. L.; Hermida, R. C.; McCormick, J. B.; Bremner, F. W.; Third, J. L.H.C.; Ryan, M.; Shirazi, P.; Nemchausky, B. A.; Scheving, L. E. Author Information

Hermida, R. C.1; Vesely, D. L.2; Kanabrocki, E. L.3; Bremner, F. W.4; Third, J. L.H.C.3; Ryan, M.3; Shirazi, P.3; Nemchausky, B. A.3; Scheving, L. E.5 Author Information

Serum homocysteine levels were examined in a 24-hour study of 7 healthy and 5 diabetic men, revealing a statistically significant circadian rhythm (p = 0.030), normal concentrations of 11.83 +/- 1.2 vs 12.99 +/- 1.2 micromol/L, with peak values occurring during the evening (10:37 P.M.) and lowest levels occurring during the morning. These findings imply that increased atherosclerotic risk in insulin-resistant diabetics during morning hours does not appear to be explained by differences in homocysteine levels in the normal population.

Long-acting natriuretic peptide (LANP), vessel dilator (VSDL), and atrial natriuretic factor (ANF) consisting of amino acids (aa) 1 to 30, 31 to 67, and 99 to 126, respectively, of the 126-aa ANF prohormone circulate in humans. Among the biologic properties of these peptides is the ability of ANF to decrease intracellular calcium concentrations. To determine if atrial natriuretic peptides are directly related to serum calcium and/or phosphate in healthy normocalcemic humans, we examined 21 24-hour profiles of VSDL, LANP, ANF, and serum calcium and phosphate in 14 healthy humans. VSDL, LANP, and ANF each had significant (P < .001) circadian rhythms, with peak concentrations late during sleep (at 4:00 AM) being nearly twice the concentrations in the afternoon and evening. Serum calcium and phosphate also had significant circadian rhythms (P < .001) with troughs nearly opposite to those of the atrial natriuretic peptides, suggesting that atrial peptides may be important in the modulation of the circadian rhythms of calcium and phosphate. The nearly identical circadian rhythms of the atrial natriuretic peptides and of parathyroid hormone (PTH) reported by others, along with evidence that PTH may increase atrial peptide release, suggest that some of the effects attributed to PTH may be mediated by atrial natriuretic peptides.

The cytokine interleukin-6 (IL-6) is a multi-functional small peptide molecule that is produced by various types of lymphoid and non-lymphoid cells and plays a central role in hematopoiesis, host defense mechanisms, and acute phase reactions, including regulation of inflammatory and immune responses. A high-sensitivity ELISA assay was applied to serum (S) and urine (U) samples available from 10 men (median age = 50y, range = 46-71y) in order to compare circadian characteristics of IL-6 between assays and in 2 biological fluids. S and U samples were collected at 3-h intervals for 24hrs beginning at 19:00h on May 14, 1993 (8 samples/subj) and frozen at -25 degrees C until analysis. IL-6 in U was adjusted for time & volume (pg/hr) and assigned to midpoint of collection interval. A significant time-effect was found by ANOVA and a high-amplitude circadian rhythm was detected by the least-squares fit of a 24-hr &/or 24+12-hr cosine for each assay. Higher serum IL-6 values were detected throughout the night, with a peak at 01:00h, and lower values throughout the day, with a nadir at 10:00h. In contrast, IL-6 values in urine were highest during the day, with a major peak in the afternoon at 17:30h and a minor peak at 08:30h, and lowest values overnight, with a nadir at 23:30h. Of interest, the rhythm in urinary IL-6 concentration (pg/ml) was more prominent than hourly excretion rate (pg/hr). Thus, endogenous IL-6 (and possibly other cytokine) levels may be significantly influenced by their large and predictable day-night variations and the biological fluid used.

Objectives. To study the circadian relationship between serum prostate-specific antigen (PSA) and total testosterone in men without clinically evident prostate disease.Methods. Blood samples were collected every 3 hours for 24 hours (eight per subject) from 11 clinically healthy men, ages 46 to 72 years. PSA was also monitored once a week for 6 weeks in 16 additional healthy men. PSA, testosterone, and age were correlated by linear regression, and 3-hourly PSA and testosterone values normalized to percent of individual mean were analyzed for circadian rhythm by the least squares fit of a 24-hour cosine.Results. Mean PSA correlated positively (P < 0.001) and testosterone correlated negatively (P = 0.014) with age and inversely with each other (P < 0.001). The mean circadian range of change (ROC) from lowest to highest values for PSA was 0.37 +/- 0.07 ng/mL (28 +/- 9%), and for testosterone it was 202 +/- 23 ng/dL (53 +/- 7%). The mean ROC over 6 weeks was 0.32 +/- 0.04 ng/mL. A significant circadian rhythm was found for PSA (P = 0.011, amplitude = 5.4 +/- 1.8%, acrophase = 5:02 AM; 95% limits, 2:40 to 7:24 PM) and testosterone (P < 0.001, amplitude = 9.4 +/- 1.8%, acrophase = 8:38 AM; 95% limits, 7:12 to 10:04 AM).Conclusions. The temporal relationship between circadian rhythms in PSA and testosterone suggests different physiologic states over the 24 hours, which may be of chronopharmacologic interest with regard to dosing time of drugs or hormonal treatments intended to affect prostate growth and function. Within-day variation in PSA is of little diagnostic significance and does not prevent accurate clinical classification when a single specimen is used.

A brief historical summary is presented regarding the emergence, over the past several decades, of chronobiology as the newest of the integrating discipline of biology. The emphasis is on the circadian system which normally is synchronized to the 24 h environmental light-dark cycle. In the absence of a suitable synchronizer, the system free runs on its own endogenous genetically determined frequency, which usually only approximates 24 h. Since the metabolic system changes rhythmically in time it follows that an organism such as man is biochemically and physiologically a different entity at different circadian stages; therefore it reacts differently to an identical stimulus given at different times. Different stimuli such as anticancer agents are examples considered clearly timed treatment has been shown to significantly improve therapeutic efficacy, data will be presented using the L1210 mouse leukemic model. Moreover data is presented showing that to ignore such rhythmic fluctuation when designing experiments that such can bring about experimental error and false interpretation. The common "same time of day" sampling does not take care of the rhythmic problem!

It is well established that caloric restriction extends life span (McCay et al. 1935; Sacher 1977; Masoro 1985; Holehan and Merry 1986) and significantly retards the rate of occurrence of most age-associated degenerative disease (Walford et al. 1974; Harrison and Archer 1983; Kritchevsky et al. 1984; Loyd 1984; Pollard et al. 1984; Pollard and Luckert 1985; Johnson et al. 1986; Ruggeri et al. 1987). The search for a mechanism(s) through which these significant benefits occur has begun, but remains elusive. However, some progress has been made and it appears that numerous processes may be involved (Walford 1983; Weindruch and Walford 1988). Changes in endocrine function (Frolkis et al. 1970; Andres and Tobin 1977; Finch 1977; Everitt 1980; Masoro 1988) and resultant regulation of certain metabolic processes have been implicated (Heuson and Legros 1972; Kmiec and Mysliwski 1983; Feuers et al. 1989).

Reports on clinical trials with subcutaneous and intrapulmonary administration of low-dose heparin suggest that it may be an attractive therapeutic modality for the treatment of coronary artery disease because of unprecedented reduction in mortality of treated subjects. As a preliminary to a clinical trial with low-dose intrapulmonary heparin, a pilot study was conducted on three subjects. It compares overall circadian responses of 37 blood variables following intrapulmonary administration of heparin (10,500-18,800 U) in the morning (0800 h) and in the evening (2000 h). After each of these times, blood samples, mostly at 3 h intervals for the ensuing 27 h, were analyzed for heparin, APTT, TT, functional fibrinogen, CBC, enzymes, lipids, electrolytes, and hormones. Each time series was analyzed for circadian rhythm by the least-squares fit of a 24 h cosine and circadian mesors were compared by the Bingham test of rhythm parameters. Following heparin in the evening, but not in the morning, a statistically significant increase in circulating heparin levels, as well as directional increases in APTT and TT and decreases in fibrinogen, were observed in all three subjects. Same direction changes in several other variables were also observed. It is concluded that inhalation of heparin in low-dose levels results in variable circadian effects on blood parameters measured, ranging from no changes in their levels to minimal within normal range changes, and that these effects are dependent upon the timing of dose administration. It is suggested that the timed self-administration of low-dose heparin by inhalation be seriously considered for long-term clinical trials in the treatment and prevention of atherosclerosis.