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1 Massachusetts General Hospital Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
2 Pharmacology Department, University of Virginia Health Sciences Center, Charlottesville, VA, USA
3 Amgen, Inc., Thousand Oaks, CA, USA
* To whom correspondence should be addressed. E-mail: sgrinspoon{at}partners.org.
To investigate the regulation of leptin secretion and pulsatility by fat mass, we performed overnight leptin sampling every 20 minutes for 12 hours and compared leptin dynamics with total body, abdominal subcutaneous and visceral fat measurements in 20 healthy male subjects. Simultaneous growth hormone (GH), cortisol and insulin levels were assessed to determine the relatedness and synchronicity of leptin to GH, cortisol and insulin in the fasted state, during the overnight period of maximal endogenous secretion. Deconvolution analyses were performed to determine simultaneous hormonal dynamics and investigate their relationship by using cross-correlation and cross Ap-En analyses. Subjects demonstrated 4.7 ± 0.4 leptin pulses in 12 hours. Leptin secretion correlated highly with total body fat (r=0.78, P<0.001) and regional fat depots. In contrast, leptin pulsatility did not correlate with total fat (r=0.07, P=0.785) or any measure of fat. There was synchronicity between growth hormone and leptin (lag of -39 minutes), cortisol and leptin (lag -211 minutes), and leptin and insulin with leptin following insulin by 275 minutes. The mean random Cross-ApEn (X-ApEn) was significant between leptin and growth hormone (0.854 ± 0.030), cortisol (0.891 ± 0.023), and insulin (0.868 ± 0.034), demonstrating a high degree of regularity and pattern frequency between leptin and the other measured hormones. These data demonstrate differential regulation of leptin secretion and pulsatility in adipocytes, and suggest that the leptin pulse generator is extrinsic to fat, whereas fat mass per se acts as an amplifier to modulate secretion and amplitude for a given pulsatility. We demonstrate synchronicity between leptin and growth hormone, cortisol and insulin. The directionality of the cross-correlation suggests a temporal construct in which changes in leptin follow those of insulin, but precede those of GH and cortisol during overnight fasting.
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