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Short-Term Fasting Selectively Suppresses Leptin Pulse Mass and 24-Hour Rhythmic Leptin Release in Healthy Midluteal Phase Women without Disturbing Leptin Pulse Frequency or Its Entropy Control (Pattern Orderliness)¹

Departments of Pediatrics and Physiology, University of Turku (M.B.), FIN-20520 Turku, Finland; Endocrinology Section, Medicine Service, Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24513; and Division of Endocrinology and Metabolism and the NSF Center for Biological Timing, University of Virginia Health Sciences Center (W.S.E., J.D.V.), Charlottesville, Virginia 22908

Address correspondence and requests for reprints to: J. D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Box 202 McKim Hall, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: JDV{at}Virginia.edu

Nutritional signals strongly regulate neuroendocrine axes, such as those subserving release of LH, GH, and TSH, presumptively in part via the adipocyte-derived neuroactive peptide leptin. In turn, leptin release is controlled by both acute (fasting) and long-term (adipose store) nutrient status. Here, we investigate the neuroendocrine impact of short-term (2.5-day) fasting on leptin release in healthy young women studied in the steroid-replete midluteal phase of the normal menstrual cycle. Eight women each underwent 24-h blood sampling at 10-min intervals during a randomly ordered 2.5-day fasting vs. fed session in separate menstrual cycles. Pulsatile leptin release was quantified by model-free Cluster analysis, the orderliness of leptin patterns by the approximate entropy statistic, and nyctohemeral leptin rhythmicity by cosinor analysis. Mean (24-h) serum leptin concentrations fell by 4.6-fold during fasting; namely, from 15.2 ± 2.3 to 3.4 ± 0.6 µg/L (P = 0.0007). Cluster analysis identified 13.9 ± 1.1 and 14.3 ± 1.1 leptin peaks per 24 h in the fed and fasting states (P = NS), and unchanging leptin interpeak intervals (89 ± 5.4 vs. 92 ± 5.3 min). Leptin peak area declined by 4.2-fold (155 ± 21 vs. 37 ± 7 area units, P = 0.004), due to a reduction in incremental leptin pulse amplitude (4.4 ± 0.7 vs. 1.0 ± 0.13 µg/L, P = 0.0011). The cosine amplitude and mesor (mean) of the 24-h leptin rhythm decreased by 4-fold, whereas the acrophase (timing of the nyctohemeral leptin peak) remained fixed. The approximate entropy of leptin release was stable, thus indicating preserved orderliness of leptin release patterns in fasting. Cross-correlation analysis revealed both positive (fed) and negative (fasting) leptin-GH relationships, but no leptin-LH correlations.

In summary, short-term (2.5-day) fasting profoundly suppresses 24-h serum leptin concentrations and pulsatile leptin release in the sex steroid-sufficient midluteal phase of healthy women via mechanisms that selectively attenuate leptin pulse area and incremental amplitude. In contrast, the pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern 24-h leptin release are not altered by acute nutrient restriction at this menstrual phase. Leptin-GH (but not leptin-LH) showed nutrient-dependent positive (fed) and negative (fasting) cross-correlations. Whether similar neuroendocrine mechanisms supervise altered leptin signaling during short-term nutrient restriction in men, children, or postmenopausal women is not known.

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