Responses of Leptin to Short-Term Fasting and Refeeding in Humans: A Link With Ketogenesis but Not Ketones Themselves

  1. Jasé F Caro
  1. Division of Endocrinology and Metabolic Diseases, Department of Medicine and the Department of Clinical Nutrition, Jefferson Medical College, Thomas Jefferson University Philadelphia, Pennsylvania
  1. Address correspondence and reprint requests to Jerzy W. Kolaczynski, MD, Division of Endocrinology and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, 1015 Chestnut St., Jefferson Building, Suite M100, Philadelphia, PA 19107.


We investigated the response of leptin to short-term fasting and refeeding in humans. A mild decline in subcutaneous adipocyte ob gene mRNA and a marked fall in serum leptin were observed after 36 and 60 h of fasting. The dynamics of the leptin decline and rise were further substantiated in a 6-day study consisting of a 36-h baseline period, followed by 36-h fast, and a subsequent refeeding with normal diet. Leptin began a steady decline from the baseline values after 12 h of fasting, reaching a nadir at 36 h. The subsequent restoration of normal food intake was associated with a prompt leptin rise and a return to baseline values 24 h later. When responses of leptin to fasting and refeeding were compared with that of glucose, insulin, fatty acids, and ketones, a reverse relationship between leptin and β-OH-butyrate was found. Consequently, we tested whether the reciprocal responses represented a causal relationship between leptin and β-OH-butyrate. Small amounts of infused glucose equal to the estimated contribution of gluconeogenesis, which was sufficient to prevent rise in ketogenesis, also prevented a fall in leptin. The infusion of β-OH-butyrate to produce hyperketonemia of the same magnitude as after a 36-h fast had no effect on leptin. The study indicates that one of the adaptive physiological responses to fasting is a fall in serum leptin. Although the mediator that brings about this effect remains unknown, it appears to be neither insulin nor ketones.

  • Received May 11, 1996.
  • Revision received June 27, 1996.
  • Accepted June 27, 1996.
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